The Peter Attia Drive - #46 - Chris Masterjohn, Ph.D.： Navigating the many pathways to health and disease - NAD and sirtuins, methylation, MTHFR and COMT, choline deficiency and NAFLD, TMAO, creatine, and more

00:00:00.000 Hey everyone, welcome to the Peter Atiyah drive. I'm your host, Peter Atiyah. The drive

00:00:10.880 is a result of my hunger for optimizing performance, health, longevity, critical thinking, along

00:00:15.940 with a few other obsessions along the way. I've spent the last several years working

00:00:19.660 with some of the most successful top performing individuals in the world. And this podcast

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00:00:28.360 more fulfilling life. If you enjoy this podcast, you can find more information on today's episode

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00:04:02.960 to listen to this. If you learn from and find value in the content I produce, please consider

00:04:08.480 supporting us directly by signing up for a monthly subscription. My guest this week is Chris Masterjohn.

00:04:14.640 I've known Chris for probably about six or seven years. He's an incredibly bright guy, and we've been

00:04:19.620 going back and forth over the past several months just trying to figure out a date when we could get

00:04:23.820 together. And I knew this was going to be an exciting episode. I also want to preface this by saying

00:04:27.760 this may rank among one of the more technical episodes that we've done, and that's probably

00:04:33.000 saying a lot given our podcast. So this is definitely one where the show notes are going

00:04:37.160 to be helpful. So Chris earned his PhD about 10 years ago in nutrition science, and after a brief

00:04:42.900 stint as an academic, he has largely devoted himself to creating just a vast wealth of information

00:04:49.940 for people to help them understand so many aspects of nutrition. I have learned so much from Chris

00:04:55.600 over the years, and I must say I probably learned more on this podcast than I learn on many of the

00:05:03.340 podcasts that I host, although I do like to learn something on every podcast and think that I do.

00:05:07.880 What do we talk about? Well, we talk about a ton of stuff. We kick this episode off by going deep

00:05:13.660 on choline. Choline deficiency is something that, as Chris explains, predisposes us to a whole bunch of

00:05:20.240 bad stuff, not the least of which is non-alcoholic fatty liver disease, which, if you've heard me rant on

00:05:25.300 this before, you realize is an enormous epidemic and is, in fact, on pace to become the leading

00:05:31.120 cause of liver transplant in the United States. Of course, that leads us into a lengthy discussion

00:05:36.420 of non-alcoholic fatty liver disease and also a detailed discussion about the different types of

00:05:42.500 fats and how they may predispose us to different types of illnesses. We also get into a topic that I

00:05:48.560 get asked about all the time, and I have purposely not gone into this in detail because I've known that I

00:05:55.140 want to have Chris on, and I want to discuss this with Chris, and those are the enzymes MTHFR and COMT.

00:06:01.840 I get asked tons of questions about these, and many of you ask questions about methylation. They're

00:06:06.380 great questions, and I think it's safe to say virtually every question you have on the topic of

00:06:10.580 MTHFR, methylation will be addressed here. We save the best for last, and again, many of you have asked

00:06:18.220 this question. Peter, what is your view on nicotinamide riboside or NMN or NAD,

00:06:22.860 SIR2 and activators, all of these things. Now, we talked about this stuff in pretty good detail

00:06:27.140 with David Sinclair on one of the previous episodes. We go a little deeper here, and in particular,

00:06:34.580 that's because since the episode with David Sinclair, there has been a little bit more research that's

00:06:39.500 been published, and we go really deep on some of those papers. So I would say that by the time you're

00:06:45.220 done with this episode, you will have as much information as one could say is available on

00:06:50.560 the use of supplemental products that contain NR or NMN. So obviously, the two of these that are

00:06:56.760 most commercially known are Elysium's Basis or Chromadex's True Niagen. Again, I want to just say

00:07:04.100 this episode is a little more technical than most of our episodes, and again, I acknowledge the irony of

00:07:09.420 that statement. That means it's really technical. The show notes will be helpful. There may be parts of

00:07:15.180 this that are more interesting to you than others, although personally, I found every minute of

00:07:19.740 this to be like drinking from a fire hose and truly learning this stuff. You can certainly find out

00:07:24.680 more about Chris and his work on his site, which is chrismasterjohnphd.com, and that's basically

00:07:31.800 spelt as you would expect it to be. John is J-O-H-N. Chris is very active on social media, loves to

00:07:37.700 interact with people. So if you haven't heard about Chris prior to this episode, I suspect you'll become

00:07:42.260 a fan of his going forward. So I hope you'll enjoy my interview with Chris Masterjohn.

00:07:49.820 Hey, Chris, thanks for trekking in, man. Thanks for having me, Peter. It's good to be here.

00:07:53.800 Yeah, so you said you've moved. You're no longer in Brooklyn, right?

00:07:56.140 I moved to Astoria, so pretty close by. Yeah. It was probably a quicker trek here from Astoria

00:08:01.900 than Brooklyn, I think. Yeah, it just has less cachet, right? Like Brooklyn is so cool.

00:08:05.840 Well, yeah, maybe I would have wanted to spend more time in Brooklyn, but no, just geographically,

00:08:12.420 Astoria is more on the edge, closer to the river. Yeah, yeah. And where'd you grow up?

00:08:17.980 So I was born in Queens, actually. I kind of came full circle back, but when I was 10 months old,

00:08:22.760 my family moved to Massachusetts. So I grew up in a small town that almost no one has ever heard of

00:08:28.420 that wasn't big enough to have its own high school.

00:08:31.080 Impressive. So not Framingham? No, no. About an hour and a half west of Framingham.

00:08:38.440 And no accent? Yeah. You can do it on demand?

00:08:41.620 No, just too far away from Boston. Yeah. Got it. And what did you study in college? I know

00:08:46.860 you're, we'll talk about your PhD because it's so interesting, but what did you study in college?

00:08:50.420 In my undergrad, I studied history. Okay. I focused on completely irrelevant things to medicine,

00:08:58.060 nutrition, like medieval church history and early American revolutionary history. I originally wanted

00:09:04.180 to be a social studies teacher. And so in my, in my vision, I was majoring in whatever was the most

00:09:11.060 efficient way to get an undergrad that would be relevant to being a social studies teacher.

00:09:15.140 I just had such profound experiences with health in my last year or two that I, by the time that I was

00:09:22.880 in my last year, I completely changed my mind, decided I wanted to go to medical school,

00:09:26.380 but I had to finish my degree. And then in order to go to medical school, which I didn't wind up

00:09:32.120 doing, but in order to go to medical school, I had to take years worth of undergrad science classes to

00:09:37.220 get the basic prereqs. And while I was doing that, a combination of my colleagues, my teachers,

00:09:44.880 me falling in love with biochemistry and molecular biology and all the little invisible things that we

00:09:49.960 couldn't see. And also me starting to come up with my own scientific hypotheses that I knew no one would

00:09:57.760 ever research them unless I did. All of that just kind of combined to make me decide to go into research

00:10:03.560 instead of, instead of medicine. So I think what I really wanted to do is take my own experiences and

00:10:09.400 pay them forward in some way. And I think the best way that I can do that is by using the creative

00:10:16.100 part of my brain to really immerse myself in the research and come up with new ideas.

00:10:21.120 Yeah. And it's funny, you know, I think I've said this before, maybe on the podcast, but if I

00:10:24.460 haven't, I know I've said it elsewhere. I always think the worst thing you can do is do in undergrad

00:10:30.760 what you're necessarily going to do in graduate school. So if you're going to go to medical school,

00:10:34.820 I've never really understood the logic of studying pre-med. I mean, I understand the logic, but

00:10:39.460 I think if you can stomach it, it's better to do something completely different. And then, and

00:10:44.840 similarly, when you're doing your PhD, I mean, sometimes you don't have a choice. You know,

00:10:47.920 if you want to do your PhD in aerospace engineering, you have to do something that approximates

00:10:51.960 engineering as an undergrad. But yeah, your story is pretty interesting in that regard. And I suspect

00:10:56.960 you're in some ways better off for having done something totally different. If nothing else,

00:11:02.140 it gave you, I suspect kind of a fresh enthusiasm for what you were studying in graduate school.

00:11:07.920 Yeah, I think for sure. And I also think to some degree, I actually bring my history mind with me.

00:11:15.080 So I think one of the things that we often neglect in science is we get so caught up in the latest

00:11:22.260 research that we forget to study the foundations of where things came from. And so my instinct is

00:11:27.220 always to say, well, where did this idea come from? What was the origin of this? And that inevitably

00:11:33.340 leads to finding a fresh way to look at something because you realize that the path that led you

00:11:39.720 there, that there were details that got left behind because no one knew what to do with those details

00:11:44.140 at that time. But then 70 years later, oh, now that that little detail that we forgot actually makes

00:11:50.320 sense now. And you can start to just get a fresher perspective than you would have if you if you only

00:11:55.260 look at what's been done over the last 10 or 20 years. You know, when I was thinking about us

00:12:00.040 sitting down together, I was having a hard time figuring out where I wanted to start because I

00:12:04.140 also I realized we run the risk of once we start on a topic, it's possible we will never get out of

00:12:09.700 said topic. But there really are several distinct things I want to get into with you. So I actually did

00:12:17.420 something I don't often do, which is I made a bunch of notes. And these notes are going to kind of

00:12:21.580 keep me honest, because they're going to at least remind me of major themes. I've used different

00:12:26.060 fonts and highlighted things. I've really nerded out on this. Why don't we start with something that

00:12:31.780 you and I have spoken about, probably six, seven years ago, which is choline. And I think the

00:12:39.820 context in which it came up was when a paper came out of Cleveland Clinic, I believe it was Stan

00:12:44.940 Hazen's paper that looked at TMAO. And it got a ton of attention. And the thesis was,

00:12:51.580 this TMAO thing is the arch enemy of your arteries, and you're going to get atherosclerosis.

00:12:57.920 And diets that are high in choline are predisposing to this. And I remember you, me,

00:13:04.240 Stefan Guyanae, Chris Kresser, we talked, we were talking a lot about this, because

00:13:07.280 certainly at the time, something didn't make sense. So we first encountered each other, right?

00:13:11.880 Yeah, I don't know if it was the first time, but it was certainly early on.

00:13:14.220 The first real email discussion.

00:13:15.760 That's right. Yeah, we had this huge email thread. And I couldn't wrap my mind around,

00:13:19.720 how could this be true if the epidemiology, which I'm not a fan of epidemiology, but in the

00:13:24.740 contrapositive, it can be quite helpful, which is every epidemiologic assessment of people who

00:13:30.100 consume high amounts of fish would suggest the exact opposite. And yet this paper would suggest

00:13:34.900 that there's nothing you could do worse than eating fish outside of choline-laced sports drinks.

00:13:41.460 So let's go back in time to that whole thing. So let's start with what is choline?

00:13:46.760 Choline, you could look at it from a health perspective or a chemical perspective.

00:13:50.260 Yeah, let's start chemically. Let's just say, yeah.

00:13:52.080 So choline is a methyl donor. Choline is an essential part of acetylcholine,

00:13:58.120 which is a neurotransmitter. And choline is an essential part of phosphatidylcholine,

00:14:02.220 which is a phospholipid that is in our cell membranes.

00:14:05.860 And I'm just going to, because I know there's half of our listeners will know exactly what you

00:14:09.880 just said, and half of them won't. But because we're going to come back to these terms

00:14:13.260 so often, what's methyl? What is a methyl group?

00:14:16.200 So I think the easiest and simplest way to think of a methyl group is to come back and look at the

00:14:23.360 fact that we are biological organisms. All biological organisms are made of hydrocarbons.

00:14:29.580 And if you look at any molecule in our body, it's mostly a string of carbons. And if you want to

00:14:35.480 synthesize one of those molecules, or you want to change one of those molecules, you're going to

00:14:39.460 have to put together carbons or take them apart. And you can either put together carbons in two

00:14:43.900 carbon units called acetyl groups, or you can put together carbons in one carbon units. And that one

00:14:48.940 carbon unit is a methyl group. And if you just think about it very simply, if you had a molecule

00:14:55.860 with an odd number of carbons, you'd have to put a methyl group in there sometime because two plus

00:15:01.120 two plus two plus two never makes an odd number. Or you might have a molecule that has something else

00:15:06.700 in it like a nitrogen and it's got three carbons attached to it. Well, the only way you can do

00:15:09.940 that is methylate that nitrogen three times.

00:15:12.120 Right. So we use the term methylation as a verb to say to put on a methyl group, right?

00:15:17.320 Right. And in fact, the methylation is also called the one carbon metabolism. So a methyl group and a

00:15:23.480 one carbon is identical.

00:15:26.220 Okay. So we've got this idea of choline plays an important role in regulating how that whole

00:15:30.600 methylation thing works. Choline is relatively abundant in certain things that we eat, right?

00:15:36.700 Yeah. If you look at the diet, you see enormous amounts of choline in liver and egg yolks. And

00:15:42.380 then you see moderate amounts of choline in many other foods. Most of those foods that are pretty

00:15:48.160 good sources of choline, but not awesome sources of choline are meats, nuts, and low carbohydrate,

00:15:57.000 low calorie vegetables, especially cruciferous vegetables. And in fact, we did not know for

00:16:04.380 the longest time that choline was an essential nutrient in humans and still they started feeding

00:16:09.900 people on total parenteral nutrition and they weren't putting choline in.

00:16:14.480 And I'll explain to folks what that is. So total parenteral nutrition or TPN is something that

00:16:19.160 is completely given intravenously, but into large central veins. And it's for people who

00:16:24.560 have such severe pathology in their gut that nothing that you trickle into their gut could ever

00:16:30.540 give them nutrition. And so you're feeding them through these large veins. And I guess where

00:16:35.200 you're going to go with this is when you're feeding someone with total parenteral nutrition,

00:16:39.400 you have 100% control over what they're consuming. And I know where the story is going. It's so

00:16:45.620 interesting. It can really expose deficiencies that we take for granted.

00:16:50.060 The same thing is true of omega-3 fatty acids or a number of nutrients that we just assumed no one

00:16:55.360 needed until we fed them on TPN without that thing. And then all of a sudden something really,

00:16:59.940 really bad happened.

00:17:00.920 So what happened with the choline deficient TPN folks?

00:17:04.520 Those folks developed fatty liver.

00:17:06.320 Which is very counterintuitive, right? In the sense that they probably weren't being mainlined a

00:17:10.760 lot of fat, right?

00:17:12.140 Right. But it turns out that because choline is an essential part of the phospholipid phosphatidylcholine,

00:17:18.700 and because that phospholipid is not just in our cell membranes, but it's also in the membranes of

00:17:22.660 the lipoproteins that carry fat out of the liver, then if you don't have enough choline,

00:17:27.720 you can't make the VLDL particle to get triglycerides out of the liver. And we think a lot about we want

00:17:36.040 triglycerides out of the blood, but we want triglycerides out of the liver too.

00:17:39.780 First and foremost.

00:17:40.500 Right.

00:17:40.620 So if choline is not there, you get fatty liver. That's not surprising in hindsight if you just look

00:17:47.760 at the animal research. Because you go back almost a century, and they had basically done the same

00:17:54.580 thing to animals. So when they started purifying animal diets, it was almost the same story. They

00:18:00.240 didn't realize these things were necessary. A bunch of problems happened. They realized the nutrients

00:18:04.300 that were necessary. And going back to the beginning of the 20th century, what we have

00:18:09.300 is rodents developing fatty liver on the diets until they were able to either put choline in

00:18:16.960 or reduce the sugar content. But in those animal experiments, what ultimately was shown was that

00:18:22.920 it doesn't really matter what the cause of the fatty liver is. As long as you have enough choline in

00:18:27.280 the diet or you have some precursor to make choline, whether it's sugar, alcohol, fat, as long as you have

00:18:32.700 enough choline in the diet, you can clear those triglycerides out of the liver.

00:18:36.040 So that's interesting. And that's something I actually wanted to explore with you because

00:18:38.880 I'm in the midst of writing this book, which I'm so sick of talking about the heck that I'm in the

00:18:43.420 middle of writing this book. I can't wait to just be done with the thing. But one of the chapters is

00:18:48.640 on kind of this spectrum of NAFLD, NASH, insulin resistance, and type 2 diabetes. So in doing that,

00:18:57.960 I went back and had to look a lot more at the history of who was the first person to describe it.

00:19:02.380 What was that index patient who first had NAFLD? And it's this sort of funny story of this character

00:19:07.280 who was drinking something to the tune of like 20 bottles of Coca-Cola a day. You know, he's just

00:19:12.220 mainlining Coke. This is back in the 50s. So you alluded to this a second ago, which is, you know,

00:19:18.000 sucrose plays an important role in this. Ethanol plays an important role in this. So the question is,

00:19:24.520 if I understood you correctly, is it safe to say that you take a person, let's just make it clinical,

00:19:29.760 take a person who has non-alcoholic fatty liver disease, and we'll talk a little bit more about

00:19:33.320 that in a second. But with NAFLD, you don't have to necessarily restrict any of the substrates

00:19:40.080 that are predisposing to more fat accumulating in the liver than exiting the liver?

00:19:45.720 That's what I would believe based on all of the animal experiments that were done. It baffles me that

00:19:52.360 we don't have human studies addressing exactly that. I mean, we have human studies that if you put

00:19:58.220 people on a, if you take what the average person is eating right now, and then you put them in a

00:20:02.780 controlled lab environment and you take the choline out of their diet, nine out of 10 of them will

00:20:06.740 develop fatty liver disease. And by the way, does it progress from fatty liver to the NASH variant

00:20:13.320 where you actually start to see the inflammation? Or is that not necessarily a place that they

00:20:18.660 progress to? Is it just the accumulation of fat? In those studies, you're looking at short-term

00:20:23.720 development of steatosis and which is just the simple fat accumulation. Based on how I understand

00:20:31.080 the physiology of fatty liver disease, what you would expect is that putting a bunch of fat in

00:20:37.580 the liver is kind of like building the kindling for a fire. So you build the fire and you don't light

00:20:43.500 it. Then that person at some point, they might not ever light that fire, but all it takes after all

00:20:51.260 that kindling, what is put into place is some hit of inflammation or oxidative stress that suddenly

00:20:56.660 lights that up on fire. And in the literature, that's called the two hit hypothesis of fatty liver.

00:21:02.720 So what you presume is not that steatosis necessarily leads to steatohepatitis, but that you can't develop

00:21:11.820 steatohepatitis without steatosis, right? So it just puts you now into this new category where there's a

00:21:17.140 fairly high probability that that will happen. But the point I want to make with these acute studies

00:21:21.600 is we know that the average person walking around out there who doesn't have fatty liver, they don't

00:21:27.900 have fatty liver because of the choline in their diet. Not because they're consuming a paucity of

00:21:33.720 the things that are uniquely fattening to the liver, the two most obvious being fructose, ethanol,

00:21:39.780 or highly abundant polyunsaturated fatty acids, things like that.

00:21:43.160 Well, it's both. But what I'm saying is in these studies that were done, I believe this was

00:21:47.300 Steven Ziesel's group, who's one of the main choline guys, they just took people randomly eating

00:21:52.760 whatever they were eating, and they didn't have any fat in their liver. And then they put them on

00:21:56.840 this experimental diet where they took the choline out of what they were already eating. So

00:22:00.600 they probably were eating some sugar, they were probably drinking some alcohol, I don't know exactly

00:22:04.840 how much. But the point is, if you're out there walking around without fatty liver,

00:22:08.540 and you can see this in the TPN too. Those people at some point in their history didn't

00:22:13.320 have fatty liver, they went on the TPN, they got fatty liver. But you don't have to put them

00:22:17.360 on TPN, you can just put them on a low choline diet. And if you look at all the animal experiments,

00:22:23.400 what they show is you can cause fatty liver with sucrose, you can cause fatty liver with

00:22:28.780 alcohol, you can cause fatty liver with fat. And no matter how you cause it, you just put in

00:22:34.740 choline or you put in things that can be precursors to choline and any of them at a high enough ratio

00:22:39.820 with the other things that are producing the fat in the liver, we'll get rid of the fatty liver.

00:22:43.760 So if we know in humans that you get fatty liver when you take the choline down, and we know in

00:22:48.960 animals that you get rid of fatty liver, if you put the choline up, then I would think that if you

00:22:55.120 took the humans with the fatty liver and you put the choline up, you'd get rid of it. But for some

00:22:58.720 reason, that hasn't been tested the way you'd think it would be.

00:23:03.160 Do you have a sense of how much choline is required in that situation? So if you took a

00:23:07.400 patient who unequivocally had fatty liver disease by say MRI, so we take the gold standard and we

00:23:13.100 could actually measure, you know, 20% of their liver was now made up of fat. And they were on,

00:23:19.340 let's say they were not on an especially restrictive diet. So they weren't someone who was avoiding

00:23:23.740 eggs or anything like that, but presumably they weren't having enough. How much choline would you

00:23:29.420 guess you'd have to put in the diet? And would you be able to achieve that through eating more foods

00:23:34.280 rich in choline or would you actually need to supplement it? I can only give you a wild guess

00:23:38.880 and my wild guess would be about 1200 milligrams of choline. And you could get that by eating food,

00:23:45.300 but it would be very difficult. So how many milligrams of choline in an egg? 130.

00:23:49.560 You don't know how many eggs I eat. How many eggs do you eat? No, well, I have chickens.

00:23:53.600 I had four this morning. Yeah, I could easily eat six eggs a day. You can do it, but it's hard and

00:23:59.240 you'd have to design the diet to do that, right? I'm basing that on a couple of things. One is

00:24:04.480 there are human studies where it has been shown that some people require 1200 milligrams of choline

00:24:10.660 a day. And those studies are not looking at liver fat, they're looking at other markers,

00:24:15.440 but people who have a genetic predisposition to need what we know is the highest choline requirement

00:24:19.620 that a human can have is about 1200 milligrams. The other way I base that is that it's been shown

00:24:24.020 with labeling studies that in, if you take a random sample of people with NASH, which is the

00:24:28.800 steatohepatitis, they have inflammation too. If you take those people and you look at their

00:24:33.460 triglyceride export, it's reduced by 75%. So if it's 25% of normal, then I look at that and I say,

00:24:40.160 well, you probably want to quadruple the ability to export triglycerides from the liver.

00:24:44.000 And it's my guess that although the adequate intake, which is the replacement for an RDA when

00:24:51.220 you don't have enough evidence for choline is higher, I think the average choline intake is

00:24:57.100 probably somewhere around 300 milligrams. What's the RDA for choline? It depends on men and women. I

00:25:02.500 might be wrong on this, but I think it's around 500, but it's a little bit higher for men. It's a

00:25:07.520 little bit lower for women. I don't remember the exact numbers. You know, the funny thing with

00:25:10.860 non-alcoholic fatty liver disease is it's hard to know the rate at which it is increasing

00:25:16.700 because like many things, it was so likely underdiagnosed. In the book, I'm actually writing

00:25:23.680 about sort of the first patient I saw that likely had it. And it was, you know, during a case when

00:25:28.860 I was a resident and we were operating on this guy. And prior to surgery, I had done all the usual

00:25:33.920 things and tried to figure out how much alcohol he drank, which you do with every patient, because you

00:25:37.980 need to understand what their requirement for benzodiazepines is going to be. And if they're

00:25:41.880 going to have withdrawal in the perioperative period. And this patient claimed he didn't drink

00:25:46.180 any alcohol and I believed him. And then we got in there and operated and his liver looked like a

00:25:50.020 fat and duck liver. And I remember thinking, I can't believe this guy lied to me. But after the

00:25:55.720 fact, you know, I went back to him and we, I said, just look, I'm not here to judge you. You got to

00:25:59.300 tell me how much you drink. And he's like, doc, I don't drink anything. And I sort of forgot about the

00:26:03.520 whole thing until 10 years later when I realized, oh my God, that was NAFLD.

00:26:07.260 Well, what year was that?

00:26:08.680 2001.

00:26:09.780 So in 1980, the Mayo Clinic published a paper in which they coined the term NASH, which came before

00:26:16.040 NAFLD. And they coined it because of that. If you read their paper, their rationale is we have doctors

00:26:24.200 that are seeing fatty liver. They assume that fatty liver happens because of alcohol. The patients are

00:26:29.380 telling them they don't drink alcohol and they're saying, you're lying to me. And the best thing that

00:26:34.600 can come from that is an argument and there could be worse. Part of it was that it facilitated the

00:26:39.800 growth of a whole body of research. But the other part of it was it allowed doctors to have a way of

00:26:45.980 thinking and talking about the person who says that they don't drink alcohol and yet they have fatty

00:26:49.640 liver.

00:26:49.880 Right. They have, they have a liver that for all intents and purposes looks grossly just like that of

00:26:53.800 someone who is about to kill themselves through a lot of alcohol. Now, Ron Busatil, who certainly

00:26:59.080 one of the preeminent liver transplant surgeons in the world said, and this was probably about

00:27:04.100 four years ago, you know, in the year 2000, something like 1% of liver transplants were

00:27:09.460 being done for NAFLD, NAFLD predisposed. Nobody needs a liver transplant if they have NAFLD, but if

00:27:14.100 you get NAFLD, NASH and cirrhosis, you do need a transplant. And that amounted to 1%. And in, I think

00:27:21.020 about 2013, 2014, he predicted that NAFLD, NASH, cirrhosis was going to be the leading cause of

00:27:30.220 liver transplant by the year 2030 in the United States as a result of two things. One, the sort

00:27:36.500 of undeniable increase we were seeing in NAFLD and of course the success of treatment for both

00:27:41.520 hep B and hep C. So it's both those things coming down and the other one going up. So my question to

00:27:45.740 you, which I apologize for how long winded it is, even if we're over diagnosing it today or seeing

00:27:52.500 it more than it was there before, it seems hard to deny that NAFLD is more prevalent now than 20 or

00:27:58.360 30 years ago. Would you agree with that? Yeah. I think even though you can't track the prevalence

00:28:03.400 over time, you can assume that the prevalence has increased over time matched to obesity because

00:28:09.040 that's the overwhelmingly predisposing risk factor. So do you believe that it is more driven by a fat

00:28:17.060 accumulation in the liver problem or choline being less prevalent in our diets and therefore more of

00:28:24.800 a clearance problem? It's hard to make an either or question about it because it comes down to fat in

00:28:31.000 versus fat out and choline is such an overwhelming factor in the fat out part of the equation. But I think

00:28:37.100 the reason that it's increasing over time, if you had the data, I really doubt that you could show

00:28:42.760 that there's been a linear decrease in choline intake over those years. And I think you probably

00:28:48.820 could show that there was a fairly linear increase in NAFLD over those years that tracked with obesity.

00:28:55.280 And I think, you know, you can look at it like what's the percentage of people with obesity who have

00:29:01.640 fatty liver or what's the percentage of people with fatty liver who have obesity? And I might have these

00:29:06.720 numbers backwards, but I think it's 67% of people who have obesity have fatty liver and 76% of people

00:29:14.600 who have fatty liver have obesity, something like that. And I think the overwhelming reason for that,

00:29:19.540 and I don't think it's the only reason, but I think the overwhelming reason for that is that

00:29:23.980 the more obese you are, the more likely you are to have visceral adiposity and the visceral fat pad

00:29:31.940 directly empties into the portal vein. And so it was a huge factor in fat in compared to the

00:29:37.820 subcutaneous fat pad. And I think that that's probably a huge factor in why, again, not the only

00:29:44.040 factor, but I think that's probably a huge factor in why the metabolic health of someone who has

00:29:48.620 relatively more visceral fat is so much worse than the person who has relatively more subcutaneous fat

00:29:55.200 is because you're basically pounding the liver with fat all the time. You don't even have to eat

00:30:01.100 anything. It's just, you're always engaging in lipolysis. You're always freeing some free fatty

00:30:05.280 acids. And if you have this gigantic tube going right into the liver, just feeding fatty acids in

00:30:11.560 all the time, then I think that's the major thing. Now, one of the challenges of studying NAFLD is,

00:30:19.780 and I can say this with some experience because I used to be involved in an organization that was

00:30:24.980 funding research in this, is removing the biggest confounder of the reduction of NAFLD, which is

00:30:31.300 weight loss. So the biggest challenge is, so let's say your hypothesis, and I think fructose is

00:30:37.420 overwhelmingly on a molecule for molecule basis, probably one of the greatest drivers of NAFLD.

00:30:42.860 When you take fructose out of the diet, very often a person is going to lose weight,

00:30:48.360 either through some reduction, you know, spontaneous reduction in intake or some other thing.

00:30:52.300 So it's hard to then say, well, with fructose elimination, you're ridding yourself of NAFLD or

00:30:59.060 dramatically reducing it. And how much of that was due to the fructose reduction? And how much of

00:31:03.160 that was due to the weight loss? Are you aware of any data that have done a great job at trying to

00:31:08.120 disentangle those two? And it doesn't necessarily have to be fructose, but it could be an input issue.

00:31:13.140 So ethanol, PUFA, fructose, an output issue, choline, or the way you describe it as sort of this

00:31:21.280 in-between visceral thing, which is visceral fat tends to decrease when adiposity decreases.

00:31:26.860 So it's almost like there's a third variable. And it is challenging in humans to figure out

00:31:32.800 how to isolate each of those.

00:31:34.840 I don't think you can do it in humans. Well, I think you could do it in humans. I don't think

00:31:38.580 anyone will do it in humans. And I don't think that there's any data out there that do do it in

00:31:42.960 humans. And I don't think anyone will ever bother to try to figure that out because what that would

00:31:47.200 require would be putting people in a metabolic ward and feeding them precisely controlled diets.

00:31:51.900 And I think this is a huge point that you're making that applies so much broader than this

00:31:55.820 discussion. Because whenever people make one change in their diet and that changes to the foods in

00:32:03.440 their diet, they're actually changing like 30 or 40 things in their diet. And they're driving

00:32:08.560 idea of what they're doing is only one tiny part of what they're doing.

00:32:13.540 And so if you look at, say, taking the fructose out of the diet, well, you know, what's the fructose

00:32:18.180 in most cases? It's a bunch of junk food. What did they eat instead? Well, either they ate nothing

00:32:21.940 instead, or they ate something different than that, which was probably better. So the average person

00:32:26.760 who takes fructose out or who takes carbs out, even if you just go on a low-carb diet, well,

00:32:32.220 your idea is that you reduced your carbs, but actually you probably increased your protein.

00:32:36.280 You probably increased your choline. You probably increased your riboflavin. You probably increased

00:32:40.940 your zinc. You probably increased a bunch of different things. And I think that the only way

00:32:47.380 to make sense out of the human data is to take all of the animal data that does have precise controls

00:32:53.360 on it and say, you know, not assume that the animal data always matches the human data, but if you can

00:33:00.120 take all the animal data and you can say, wow, everything that is in the human data makes perfect

00:33:05.960 sense according to what the theory we get out of the animal data is, then that's what you do,

00:33:11.600 right? So when we're talking about fructose, when I was in graduate school, I fed rats a 60%

00:33:18.100 fructose diet, and I was hoping that they would get fatty liver. And I was hoping that I would

00:33:23.860 actually what I was- Wait, 60% fructose or sucrose? Fructose.

00:33:28.400 How can they even digest that? I mean, how do they not just get such severe dumping syndrome

00:33:33.220 with so much fructose? They might've had a little bit less digestion because they were a little bit

00:33:38.360 leaner. I was going to say, I mean- But that's not the point. The point is there are studies out

00:33:42.580 there showing a 60% fructose diet causes fatty liver. And did you see it in yours? No. Because you

00:33:47.520 had lots of choline, do you assume? Well, I wasn't trying to have lots of choline,

00:33:50.440 but in my department, we never fed rats or mice on casein diets, which is what almost every rodent

00:33:57.640 study out there is. Casein being the dominant protein that you would see. Yeah. But every

00:34:03.380 rodent diet is based on casein almost. I didn't even know why we did this. It was just tradition

00:34:08.700 in our lab and in our whole department that we never used casein. And later I talked to my department

00:34:13.500 head about it and he said, well, I've seen studies showing that casein is inflammatory in rats and it

00:34:19.740 causes copper deficiency. So we just prefer to avoid it. So then I look into the amino acid

00:34:25.920 composition of my diet versus the casein diets that everyone else is using. And it's something

00:34:29.920 like six times more methionine, which is a choline precursor that has been shown in animals to obliterate

00:34:37.520 fatty liver. Something like six times more methionine in my diet. So all of a sudden my negative finding

00:34:44.800 makes perfect sense with everything else that I'm looking at. And part of the reason that I have

00:34:51.880 a unique perspective on this goes back to what we were talking about at the beginning about getting

00:34:55.180 a historical perspective. I was writing a review on fatty liver with my doctoral advisor and I was

00:35:03.040 obsessive about needing to know the origins of the methionine and choline deficient mouse model.

00:35:09.420 So I went all the way back to the turn of the century. And what they found originally was

00:35:15.640 you could produce fatty liver in rodents if you fed them an 80% sucrose diet, if the nutrients came

00:35:23.020 from whole foods that they were using before, like yeast and cod liver oil and things like that.

00:35:29.060 Then when they started producing chemically defined diets, all of a sudden 50% sucrose was causing

00:35:34.420 fatty liver. And so then they said, oh, we need to reduce the sucrose. So they reduced it further.

00:35:40.680 But then people who took those same high sucrose diets at that time showed that you could add

00:35:45.920 choline, you could add methionine, which is a choline precursor. You could just up the protein.

00:35:50.800 If you just up the protein, which has methionine, which is a choline precursor, right? If you provide

00:35:57.420 any of those precursors, it just gets rid of the fatty liver. So I take those things and I look at the

00:36:03.860 human data and I say, well, that person reduced the fructose in their diet. I believe that's a

00:36:08.120 contributor because fructose compared to starch is more lipogenic. And in fact, one of the animal

00:36:13.880 models that you use for fatty liver is called the methionine and choline deficient mouse model.

00:36:18.560 Well, it's not just deficient in methionine and choline.

00:36:21.100 Yeah, they have to go to sucrose.

00:36:22.280 It's also got, yeah, it's also got a bunch of sugar in it and it's got a bunch of corn oil in it.

00:36:26.820 And they have shown that you can reduce the fatty liver if you replace the sugar with starch.

00:36:33.860 So when I look at the human data, I'm going to say, I do believe that reducing the fructose is

00:36:38.880 going to reduce the amount of fat that the liver is producing from sugar. But I also believe that

00:36:46.620 if you did that and you replaced it with protein, then that was part of the results. Or if you

00:36:53.400 replaced it with vegetables or you replaced it with egg yolks, those were part of the results.

00:36:58.340 Right. And to your point, it's very difficult. So when you look at the study that just came out

00:37:01.400 in JAMA two weeks ago, which actually was the one that way at the beginning I was involved in the

00:37:06.520 funding of, but I had no involvement in the study whatsoever. It didn't, I mean, I had to read about

00:37:10.360 it like everybody else when it came out in JAMA, but this is the one that Miriam Voss Emery was the

00:37:14.180 first author on. This is the study that took 40 Hispanic boys with biopsy proven NASH and for eight

00:37:20.980 weeks put them on a virtually zero fructose diet with no instruction to reduce carbohydrate. In fact,

00:37:27.380 the idea was replaced fructose with glucose to your point, right? Glucose is not going to produce

00:37:32.420 fatty liver in almost any quantity. They saw a 50% reduction on MRI in liver fat. But if you want

00:37:40.580 to be technically rigorous, they lost three pounds on average. Now, I don't know that the three pounds

00:37:45.800 matters that much, but I think your broader point is they almost assuredly cleaned up the quality of

00:37:51.900 their diet in ways that's difficult to measure, even just looking at the macros. Because I think

00:37:58.180 it's easy to report the macros in a study like that. Well, carbohydrate content was unchanged,

00:38:03.780 you know, protein went down a little, fat went up a little or vice versa. But at the micronutrient level

00:38:09.120 or at the amino acid level, I just don't think that stuff's being tracked. It would be interesting.

00:38:13.680 Again, I don't know, and it might even be worth you contacting Miriam Voss, who I've met twice,

00:38:19.240 and she seems, you know, very collaborative and interesting. And it might be worth understanding

00:38:24.080 what other data they would have with respect to the nutrient, because I'd be curious to dig further

00:38:29.420 into this point. Yeah. And if they have food data, if they were collecting, what are they eating for

00:38:34.120 foods? Well, the food was provided. Oh, I'm sure they could go back. If they have what the foods were,

00:38:40.260 I'm sure they could go back. Yeah, this was a very well-controlled study in that the food was

00:38:44.360 provided, not just to the children, but to their entire families. The idea was make it so easy for

00:38:51.140 the child to be compliant for the eight weeks that they were on this diet, that the entire family is

00:38:55.000 going to get fed the same food. Yeah. So they have to know what they were providing in order to

00:38:59.200 estimate the macros. So they must be able to estimate the micros. That would be interesting.

00:39:02.360 Yeah. I'd like to see that because I remember when I read it, I was really hoping that the results

00:39:07.800 would come out independent, like that there would be no change in weight, that the kids could

00:39:11.200 maintain their body weight. And then you could ask the question, could this nutritional intervention

00:39:16.340 alter NAFLD independent of adiposity? Okay. So now let's go back to where we started, right? So

00:39:22.640 you've, you've made this great case for choline and its importance. And I've always found the TPN stuff

00:39:28.460 to be one of the most compelling reasons. Cause you just don't get, you don't often get in life a

00:39:33.400 chance to create a truly deficient model in humans. So now let's talk about this thing called TMAO.

00:39:39.280 What is it and how did it rear its head into this discussion? And all of a sudden

00:39:43.700 choline became public enemy number one. Before these studies came out from the Cleveland Clinic,

00:39:49.060 TMAO was mostly known in being found naturally in fish and in being produced in the gut in very rare

00:39:58.560 cases where there were people with genetic disorders. And I don't even remember off the top of my head

00:40:02.880 what those genetic disorders were, but they were feeding them absolutely massive amounts of choline.

00:40:06.880 And so it was known before that, that in those cases of enormous choline loading,

00:40:12.360 some of that choline would be converted to trimethylamine by gut bacteria. And that that

00:40:18.320 trimethylamine, and actually the interest was largely in the trimethylamine because the trimethylamine is

00:40:24.360 the more smelly compound. So this would produce fish odor syndrome. These people are smelling like fish.

00:40:29.220 So that was what was known about it at that point. But then in 2011, I think was the first paper,

00:40:36.780 the Cleveland Clinic came out with experiments, I think in first in mouse, but also in humans showing,

00:40:44.100 well, showing different things. So in mice that were genetically engineered to have defects in their

00:40:50.380 lipoprotein metabolism, they showed that TMAO was directly atherogenic. And in humans, they showed

00:40:58.120 that in there were two different papers, the first one looked at choline and the second one looked at

00:41:05.340 meat. But what they were showing was that TMAO levels in humans correlate with heart disease risk.

00:41:12.360 And when humans eat either choline or carnitine, they will metabolize both of those to trimethylamine

00:41:22.200 in the gut and the liver will convert it to TMAO. And so the argument is the TMAO in those humans

00:41:29.380 will cause heart disease the way that it causes heart disease in the genetically engineered mice.

00:41:34.920 And if I recall, there were basically three ways that they were suggesting you could get

00:41:39.400 too much of it. One was too much fish. If you eat fish, you're getting the TMAO.

00:41:43.460 I don't think they mentioned fish.

00:41:45.140 Maybe I'm confusing it with a different paper, but I thought one argument was too much fish is

00:41:49.200 too much TMAO. Too much carnitine, which is found in sports drinks, is going to be converted and too

00:41:54.580 much choline. So basically any of those three that were too many were problematic. Now, maybe this was

00:42:00.120 stretched across a couple of different papers too.

00:42:02.180 So my recollection is that I brought the fish up because my argument was it's really easy to

00:42:09.360 just look at this stuff and say, and repeat what we already believed about eggs and red meat

00:42:15.340 being bad for you. And if you isolate it to that, it kind of makes a clean story, but it makes a really

00:42:21.500 bad story if you bring fish into the equation. Because fish have so much TMAO that you're probably

00:42:27.720 literally getting hundreds of times more TMAO exposure when you eat fish than when you eat those

00:42:32.320 foods. So my point was always, how can you not bring fish into the discussion?

00:42:38.440 Yeah. So now it's coming back to me. You wrote a piece on this that I think we'll be sure to link

00:42:45.760 to. I think the reason I had seen this fish issue separately was I was actually at an advisory meeting

00:42:52.440 for a company that had asked me and a dozen other people a question, which was, should we be using TMAO

00:43:00.280 as a new biomarker for cardiovascular disease? And so it was part of this two-day meeting where we're

00:43:05.900 sort of in this room looking at all of the data that somehow this, someone else, and I don't

00:43:11.080 remember who it was, came up with the idea of, well, wait a minute. I mean, we got to take a step

00:43:15.080 back here. I mean, if fish has more TMAO than you could ever get from all of the red meat and eggs in

00:43:22.280 the world, it converting to TMAO, it just seems to fail on first principles.

00:43:27.800 Yeah. And there were later papers that happened after those first two where there was some

00:43:32.480 observational data showing that people who eat more fish have more TMAO in their blood.

00:43:36.480 I still get asked about this, I don't know, twice a year a patient will bring in a copy of that paper.

00:43:42.300 I think it was in Nature or Nature Communications or something like that and say, oh my God, Peter,

00:43:47.400 like, what do you think about this TMAO thing? And it's just always one of those things where I kind

00:43:50.740 of eye roll and I just sort of send them a link to what you wrote or what Chris Kresser and say,

00:43:55.160 go and read this and then come back to me and let's discuss why I am not particularly impressed

00:44:00.640 by this thesis. On a scale of one to 10, I wouldn't say that my opinion that TMAO has negative

00:44:08.960 properties in humans is zero. I think it's maybe one or two or something like that. And I'm willing

00:44:14.820 to see what they come up with there. But on a scale of one to 10, my view of the overall story that

00:44:23.400 eating eggs and meat are bad for you because they alter the microbiome in a way that makes you take

00:44:30.180 the choline and the carnitine in those foods and convert it into TMAO and make you as a red meat and

00:44:36.040 egg eater uniquely vulnerable to heart disease. I'm very close to zero on the probability of that

00:44:42.000 story being true. I'm totally open to seeing new studies on the ability of TMAO and plasma to be a

00:44:49.380 biomarker and the potential for maybe eventually altering the gut microbiome in a way that generates

00:44:57.100 more TMAO. And actually, I incorporate this on a practical level in some cases. So when I'm looking

00:45:03.240 at choline supplements, I overwhelmingly prefer that someone would get phosphatidylcholine, which is the

00:45:08.760 overwhelming form of choline that's found in food for two reasons. One is it's the overwhelming form of

00:45:14.260 choline found in food. And the second is that it's the form of choline that's least likely to generate

00:45:19.360 TMAO in the gut, almost exclusively driven because its absorption is better. Do you dose it milligram

00:45:24.120 for milligram? In other words, if you believe that 1200 milligrams of choline is necessary. No, and actually

00:45:29.940 that's very confusing on supplements because most supplements of phosphatidylcholine tell you the

00:45:34.280 amount of phosphatidylcholine in them. So you don't know how much choline is there? No, you do. You can

00:45:37.680 estimate that's about 15%. Just by molar weight, it's about 15%. Right. Okay. Yeah. I mean, it's probably

00:45:42.620 an imperfect number because probably most of the time the fatty acids are different in each molecule,

00:45:50.100 right? So it's just an average, but it's close enough, right? But directionally then you would want

00:45:54.840 like nine or 10 grams to hit your 1200 milligrams. Yeah. I mean, it's only practical if you're taking

00:45:59.460 tablespoons of lecithin. Yeah. But you can get food. So you could eat eggs, right? Yeah. So eating eggs and

00:46:06.780 eating foods is the best way to get choline in my opinion. But if I were to take someone in a

00:46:11.900 particular situation where for some reason they had one or two dietary restrictions in this way that

00:46:17.580 made them not be able to get choline and you, but they needed choline for these other reasons and

00:46:21.080 you had to supplement, I would do it with lecithin for those reasons. And one of the reasons is that

00:46:27.900 I don't know whether the increased TMAO that's generated when you take choline by tartrate is

00:46:33.940 problematic. Bob, the show notes guy, he sent me a paper that was just recently published where

00:46:39.800 they fed people 500 milligrams of choline by tartrate over the course of two months. And

00:46:46.220 they did an in vitro assay on their blood and showed that it was more sensitive to clotting.

00:46:52.500 So it's the level of that evidence isn't super strong, but it's an indication that maybe having

00:46:57.500 that level of TMAO in your blood is bad. But you cannot get that level of TMAO in your blood

00:47:04.700 by eating four eggs, which supplies the same amount of choline. How do I know?

00:47:09.260 Because Steven Ziesel's group did a study looking at plasma TMAO response to eggs.

00:47:14.080 And if you eat enough eggs, you get a plasma TMAO response, but it's three or four times lower than

00:47:18.260 when you eat the same amount of choline as choline by tartrate.

00:47:20.400 And it's only anecdotal, but at the time that I was involved in this discussion around developing an

00:47:26.140 assay for TMAO, it was during that three, three and a half year window when I was on a really

00:47:30.600 strict ketogenic diet. And I was so, I mean, relatively speaking, hypercaloric because I

00:47:36.840 was also really active at the time. I needed about 4,000 calories a day. Now, 4,000 calories a day on

00:47:41.120 a ketogenic diet means you are really having to limit your protein and carbohydrate. So I was about

00:47:47.680 two to 3% carbohydrate and about eight to 10% protein and the rest was fat. So it was on a, you know,

00:47:54.340 what we would now call a four to one ketogenic diet. Although I didn't at the time think of it that way.

00:47:59.540 My point is one of the ways that I would, I had to make eggs is I couldn't just take 12 eggs and make

00:48:05.440 scrambled eggs. That was too much protein. So I could only eat, you know, I'd have like maybe four

00:48:10.440 whites, eight yolks, and then I'd have to fluff it with heavy cream. So the point is I was mainlining

00:48:17.320 this stuff. And when the lab was sort of kicking around the idea of developing the assay, I said,

00:48:23.560 I had already done some work with them where we had done like nine blood draws on nine consecutive

00:48:28.760 days under various conditions and they already had the serum. I said, well, let's look at the TMAO

00:48:34.420 levels in there. That should be a pretty good positive control. And interestingly, I had virtually

00:48:39.700 none. Yeah. Well, in that study that I mentioned, looking at the plasma TMAO response to eggs,

00:48:46.320 there was enormous variability and some people didn't really get, I think everyone got some response

00:48:53.220 to six eggs, but there was a lot of variation around the four egg mark. So half the subjects

00:48:59.780 didn't get any response at all until they ate four eggs. But some of the people got a very significant

00:49:05.580 response to the four eggs, which is what you'd expect based on what the Cleveland Clinic group

00:49:10.620 is arguing, which is that the gut microbiome is a big determinant.

00:49:14.040 Well, and that was sort of my conclusion, which is, again, it was a very deep look into one

00:49:19.180 individual, me, and that's irrelevant because any one individual is irrelevant. But the thinking was,

00:49:26.320 I got to be honest with you, I still don't know what gut health means. Like the concept is so,

00:49:30.520 you know, it's so difficult for me to, an amorphous to describe, but my intuition was something in my gut

00:49:37.540 was really preventing this from becoming problematic. I didn't know what it was. I didn't know if it could be

00:49:43.060 replicated, but the story seemed a lot deeper than, than it was being presented.

00:49:48.200 Yeah. I think one important point is that it's not about how many eggs you eat in a day. It's

00:49:52.320 about how many eggs you eat at a sitting. So the only reason eggs generate TMAO is because

00:49:57.340 there's some poorly characterized absorption cap to phosphatidylcholine. And even though it's better

00:50:03.480 absorbed than the other choline that's sold on the market, there's some cap to how much choline you

00:50:08.240 can absorb and no one really knows where it is.

00:50:10.180 Um, where is it absorbed? Which transporter is it? Is it an enterocyte transporter off the top of my

00:50:15.720 head? I don't know, but it's gotta, yeah, it's gotta be in the small intestine. Does it come as a single

00:50:21.560 phospholipid or is it esterified in some way? I mean, how does it actually come in from food?

00:50:29.460 You mean how it's absorbed or how you eat it?

00:50:31.580 So if you're eating, you know, a food that's high in phosphatidylcholine, does it actually show up

00:50:35.600 like the analogous free fatty acid or does it show up more as the analogous triglyceride where you get,

00:50:41.780 you know, say two or three of these bound to a glycerol bound to other fatty acids? Like,

00:50:48.420 do these things actually show up as free phosphatidyl molecules?

00:50:52.700 So I believe that most of the phosphatidylcholine in most of the foods is going to be as phosphatidylcholine

00:51:00.240 that are in cell membranes.

00:51:01.560 I see. Okay. No, you've answered that question. Okay. So that's what I was wondering if it came

00:51:05.460 in a more whole state or if it ever actually showed up like, so first of all, does it come

00:51:11.040 in through a chylomicron?

00:51:12.700 I assume so. I haven't looked at the absorption pathway for a while, so I might not be remembering

00:51:17.940 the details here, but my guess is that you're going to have partial hydrolysis of some of the

00:51:23.180 fatty acids and then that the phosphatidylcholine is mostly going to wind up making its way into

00:51:28.600 the mixed micelles and it's going to become probably part of the membrane of a chylomicron

00:51:34.660 would be my guess.

00:51:35.800 Right. But coming in the lumen of the gut, and I get probably not even that relevant at this

00:51:40.520 moment why, I guess I'm just trying to figure out what the, if the bottleneck is at the

00:51:44.540 enterocyte transporter and that's why you're limited in how many of these things you can

00:51:49.300 get into the enterocyte, which then on the backside go into the chylomicron.

00:51:53.880 Right. That makes sense. I mean, back when I was trying to figure this out, I asked Steven

00:51:58.140 Ziesel about this, who, if anyone knows about choline absorption or anything else about choline

00:52:03.140 it's him. And he wrote back and was like, I, you know, I really don't know. I assume that

00:52:08.100 there's some absorption cap in the small intestine. I have no idea what it is.

00:52:12.120 Wow. Interesting. So the choline story is interesting. And I think if you look at it

00:52:18.700 overly simplistically, you could say, well, it's a good guy and a bad guy, but it seems to be more

00:52:22.420 of a good guy than a bad guy, huh?

00:52:24.200 Yeah, I think so. I mean, certainly from the perspective of fatty liver, that's clear.

00:52:28.380 Yeah. Now we don't see, I'm assuming, although I've never looked at this, in people who you would

00:52:34.440 expect to have huge choline deficiencies, which would be, you know, someone who's eating a very

00:52:38.440 strict vegan diet, right? So by definition, they're not eating any liver. They're not eating

00:52:42.860 any eggs. They could certainly be eating lots of nuts.

00:52:45.320 Nuts and cruciferous vegetables they could be eating.

00:52:47.640 Now, but let's assume they're on like the college vegan diet, right? Which is like, you know,

00:52:52.360 they're eating as much crap as possible that has no animal matter in it. Is there data that would

00:52:58.520 suggest we would see a higher incidence of fatty liver in that population?

00:53:02.460 I have no idea if that data's out there. My guess is you probably wouldn't because probably

00:53:09.400 those vegans aren't too fat, but I don't know.

00:53:12.820 And this comes back to your point, which is there's just something about adiposity if it's

00:53:18.540 accompanied by visceral fat that is really stoking the fire.

00:53:22.800 Yeah. I mean, if you take out all the fat in parts of the equation, then there's just,

00:53:28.420 the choline is not going to matter that much. It's just that it becomes the bottleneck to getting

00:53:33.360 fat out when you have a buildup of fat in.

00:53:36.780 So what do you think are the role of different fatty acids in this problem? And I guess we'll

00:53:40.680 just define it for the listener, right? So we sort of loosely characterize fatty acids as either

00:53:46.000 saturated, monounsaturated, or polyunsaturated. We can further divide the polyunsaturated into a

00:53:51.600 number of constituents. I always think it's important that people sort of demystify this stuff.

00:53:55.700 And we're so quick to demonize one versus the other. But it's, as you said at the outset,

00:54:00.320 it's really just a bunch of really fun biochemistry. A saturated fatty acid is specified

00:54:06.180 by the number of hydrocarbons. The number of carbons it has, that's the chain. So a C8 versus

00:54:11.720 a C12 would have eight versus 12 carbons. But being saturated just means there are no double bonds.

00:54:17.900 Every carbon is fully saturated with a hydrogen. And then of course you can finish the explanation

00:54:24.480 for what a monounsaturated fat is.

00:54:26.320 Right. A monounsaturated fat has one double bond. A polyunsaturated fat has two or more

00:54:30.260 double bonds. That introduces a couple things. So one thing is that whenever you introduce a

00:54:36.440 double bond, you create a kink in the molecule. So saturated fats are really, you can imagine them

00:54:41.220 as it just being straight and linear and you can pack them together very well. So saturated fats tend

00:54:46.060 to be solid. Less saturated fats, fats that are higher in monounsaturated and polyunsaturated fat

00:54:51.540 tend to be more liquid. So olive oil is more liquid than butter because it's mostly

00:54:55.460 monounsaturated fat. If you take olive oil and you put it in the refrigerator and you take

00:55:00.300 corn oil or sunflower oil and put it in the refrigerator, eventually the olive oil is going

00:55:04.140 to harden and the sunflower and sunflower oil wouldn't. And that's because the sunflower oil

00:55:10.280 is more polyunsaturated and that has even more resistance to packing together. The other thing is

00:55:15.040 that in a fatty acid with two or more double bonds, so polyunsaturated fat, the carbon that's between

00:55:22.640 two of those double bonds is very unstable and it is uniquely vulnerable to being damaged. And we call

00:55:30.020 that damage lipid peroxidation. So that fatty acid is not harmful in and of itself. And in fact,

00:55:37.640 there are polyunsaturated fatty acids that are absolutely essential for us.

00:55:40.840 You alluded to these earlier. We'll come back to them, which is the omega-3.

00:55:44.700 Right. Well, I know omega-6. There are omega-3 and omega-6, both polyunsaturated. They're both

00:55:50.140 essential to human physiology. But it's also the case that the more of these that you have in your

00:55:54.840 cell membranes, the more of a liability it becomes. Because if you have oxidative stress,

00:56:00.240 if you have inflammation, then all of a sudden those fats are more vulnerable to damage.

00:56:04.580 And it's very, very tricky when you're talking about fatty liver. Because there was a human study

00:56:12.900 that was about two weeks long that was published when I was in graduate school. So maybe 2010 or 2009

00:56:20.260 this was. They showed that over the course of a couple of weeks, polyunsaturated fats compared to

00:56:26.240 saturated fats lead to less liver fat. And they used MRS. So it was highly reliable data that they

00:56:35.580 had. And if you just take that at face value, you say, well, there's one study that looked at it in

00:56:42.520 humans. There's a couple of observational studies overall. PUFAs are what you want to eat for fatty

00:56:46.640 liver. There's a problem with that, which is that if you have fatty liver, and it's mostly PUFAs,

00:56:55.840 you are way more vulnerable to progressing from steatosis to steatohepatitis because...

00:57:03.280 You have more oxidative targets.

00:57:04.700 Right. Yeah. So if you look at the animal data, it depends on the model. Generally, you get more

00:57:11.380 steatosis with longer chain length and more saturation. And you get less steatosis with

00:57:17.680 shorter chain length or with less saturation. But if you have the steatosis, you have a dramatic

00:57:24.720 increase in the risk of progressing to steatohepatitis. However, in the alcoholic model,

00:57:31.820 there are studies showing that you get less steatosis with saturated fats and with polyunsaturated fats.

00:57:36.160 I think the reason for this is that oxidative stress does not just cause you to go from

00:57:45.020 NAFLD to NASH. It also can cause steatosis because you get oxidative destruction of the ApoB particle.

00:57:55.000 And so it's not just choline that allows you to export triglycerides from the liver. You also need

00:57:59.880 sufficient antioxidant protection in the liver because if you damage that particle before it ever

00:58:04.200 exports to triglycerides, then you prevent it from doing so. I think the way you reconcile

00:58:09.160 these different animal models is you say, well, in the alcoholic model, there's so much oxidative

00:58:13.060 stress already that's provided by the alcohol because the alcohol isn't just a way to get fat

00:58:17.900 in the liver. The alcohol's metabolism generates oxidative stress. So you're taking a liver that

00:58:25.120 doesn't yet have fat accumulation. You're putting a bunch of fat into it and you're adding on top of

00:58:31.600 that in oxidative flame. So you actually wind up causing steatosis by causing oxidative damage to

00:58:39.820 the ApoB particle so that they can't leave the liver in that model. So PUFAs, I think, are very

00:58:45.660 complicated to think about because in the short term, in someone who doesn't have a lot of stuff going on

00:58:52.640 in their liver, they're probably going to be better if you look at a two-week study. And we have the data

00:58:58.480 in humans showing that. But I think in the long term, if you're talking about the progression

00:59:02.320 from steatosis to NASH, they're a clear disadvantage. And I think if you're not talking

00:59:07.800 about the healthy person who's got nothing wrong with them, then they're, who knows? It's like 50-50.

00:59:13.460 But in this two-week study you're talking about, presumably the subjects were fed disproportionately

00:59:18.420 high amounts of PUFA versus SFA?

00:59:21.020 Yeah.

00:59:21.420 Do you recall like the magnitudes that they had to be fed to produce this phenotype?

00:59:25.740 I don't recall the magnitudes, but they weren't ridiculously out of proportion to them.

00:59:29.860 They weren't super physiologic.

00:59:31.620 No, no, no. They were basically the typical amount of fat that someone would eat,

00:59:36.320 but they controlled the fat intake. So maybe people would prefer to mix the types of fats

00:59:41.360 that are in their diet. But in that case, it was atypical. But they weren't feeding them 80 or 90%

00:59:47.440 fat diets.

00:59:48.320 You know, it's interesting. You mentioned the ApoB issue. ApoB is used, obviously, in two ways in the

00:59:54.880 liver. The first way we've talked about, which is VLDL export, which is our main way to get

01:00:01.880 triglycerides out. But also we make de novo LDL in the liver. And so in those patients, do we see

01:00:08.400 a reduction in LDL as well?

01:00:11.580 I don't remember.

01:00:12.760 That's interesting. I feel like I want to start paying a little closer attention to this.

01:00:16.400 I can't even remember if they measured that.

01:00:19.600 I just haven't clinically seen that because I do see NAFLD all the time in the practice. Usually

01:00:26.120 you suspect it with an elevated ALT disproportionate to AST, and then an ultrasound will confirm the

01:00:32.620 diagnosis. Very rarely do you need an MRI and certainly never a biopsy. But I haven't seen

01:00:38.580 the association with an alteration in VLDL, which we can estimate. And obviously we can measure

01:00:45.060 triglycerides in LDL. It's also confounded, by the way, by different ethnicities. So, you know,

01:00:52.800 when you look at African-American patients, even with type 2 diabetes will still have very low VLDL

01:01:00.940 and triglycerides. A Hispanic patient with diabetes will generally have a high triglyceride and a high

01:01:08.540 VLDL. And actually they're far more susceptible to NAFLD than African-American and Caucasian is in

01:01:14.860 the middle. Are you familiar with any of the data on some of those differences as it pertains to the

01:01:20.600 lipidology of these folks? I just haven't paid attention to it myself.

01:01:24.060 No, I'm not. And can we rewind a minute? What haven't you observed with VLDL? You said you

01:01:29.260 haven't observed the association between blood levels of VLDL and NAFLD? And NAFLD, yeah. What

01:01:34.980 would you expect to see that you didn't? I would have expected, based on what we're saying, to see

01:01:39.300 a reduction in VLDL. The more NAFLD they have, the less VLDL based on this idea.

01:01:44.460 Well, I think the problem with that is that... I mean, I have an explanation for why that might

01:01:49.040 not exist. And here's the explanation. In an ideal world, that might make sense. But there's another

01:01:55.680 thing that's going on. If you have NAFLD, you are very likely insulin resistant. If you are insulin

01:02:01.400 resistant, you are upregulating APOC3. If you are upregulating APOC3, your VLDL are going to stick

01:02:08.780 around a hell of a lot longer than if you do not. And that's why we see these pathologic remnant VLDL

01:02:16.480 particles that become atherogenic. So when you or I, presuming we're both insulin sensitive,

01:02:21.380 our VLDL really don't pose much of an atherogenic risk because they stick around for such a short

01:02:26.960 period of time. So we don't have many of them. They don't stick around long. Our APOC3 is quite

01:02:32.460 downregulated. But if APOC3 is upregulated and it's hard to measure this, although Sam Tamikas is

01:02:39.400 working on an assay to do so, you have VLDL now start to act like LDL. They stick around long enough.

01:02:45.740 They have a high enough residence time in the plasma that they become atherogenic. And so I do wonder

01:02:49.820 if maybe why I don't, not that this is scientific, but the reason even my gestalt is not to see that

01:02:57.320 is maybe the less VLDL that's being exported in that patient because of the reasons you've described

01:03:03.620 is offset by a longer residence time due to more APOC3. Right. And wouldn't you also expect that from

01:03:10.780 lower rate of uptake of triglycerides from peripheral tissues?

01:03:14.720 Yeah, that's a great point. You have a lower peripheral disposal of triglycerides. So the

01:03:20.460 whole thing could be confessed. In other words, it's a great point you raise. Actually, we should

01:03:23.560 take a macro step back. This is a problem of flux and people struggle to understand flux because you

01:03:31.480 can't understand flux with a snapshot. You have to have the goddamn video, right? I mean, that's the

01:03:37.100 analogy. You can't, you take a picture of something, you don't know the flux, what's in, what's out,

01:03:42.280 where it's being disposed of. I love this point. And one of the analogies that I like to use is

01:03:46.680 although you can't use the picture, how much information you have in a snapshot can have a

01:03:52.100 huge effect on your ability to know what's going on. Now, imagine that you have a picture of a car

01:03:57.460 accident. Well, if you zoom in to the tire, you might not, and you need to look at that. You don't

01:04:03.280 know what happened. You might not have any idea what happened. The more you zoom out and the more

01:04:06.820 different angles that you have, at some point, you can start to build a story of what probably

01:04:12.160 happened based on that snapshot. But if you're looking at one element in the snapshot, you can

01:04:17.180 never even so much as build a story about what probably happened. And I think that, yeah, the idea

01:04:23.820 that mistaking a concentration for flux is one of the overwhelming interpretive problems in science

01:04:34.180 and in popular science, in both. Yeah, one of my biggest pet peeves. So every quarter when I do one

01:04:40.500 of these seven-day fasts, I get a lot of blood work done on myself throughout the process. And I get a

01:04:46.340 real kick out of it because by the time you're five, six, seven days into water only, you start to look

01:04:52.560 like there are things that if looked at in isolation look horrible. For example, your free fatty acids get

01:04:58.500 into the diabetic range. So if you show that to somebody, they think, oh my god, you're diabetic. And

01:05:03.920 you're like, really? My insulin is unmeasurable. My glucose is 60 milligrams per deciliter. Yes, my

01:05:10.240 FFA is two millimolar, but my BHB is, you know, seven or, you know, five millimolar. Isn't it possible

01:05:18.980 that what you're seeing is an incredible turnover of lipolysis? And so, yeah, there's a lot of free

01:05:24.380 fatty acid there, but it's in motion. It's in transit versus what I think is probably happening in the

01:05:29.960 person with high FFAs who's got diabetes, which is a much more stagnant form of elevated FFA. And so that's

01:05:36.900 a muscle that's full of fat that's going nowhere versus the fasted person where that fat is being turned

01:05:43.420 over very quickly. And would you rather drink water out of a stream or out of a sitting pool with

01:05:48.520 mosquitoes all over it? Exactly. So no, it's a good point. And I like your point, which is, look, the picture

01:05:54.560 can be helpful, but it has to be taken from a distance, right? So if you just look at one tread

01:06:00.900 of the tire in a photo, you're probably going to have no clue what caused the accident. If you look

01:06:06.160 at a huge picture, you could at least see where the skid marks are of both vehicles. Ultimately,

01:06:11.320 there's no substitute for having a video of the accident. And those turn out to be the hardest

01:06:15.960 things to do biochemically is to generate tests that can actually show you the movement.

01:06:22.500 Well, biochemically, what you do know, though, is that we've mapped out elsewhere biochemical

01:06:28.860 pathways. If you know all the possible sequences, and you can measure all the metabolites, you can

01:06:34.040 often reconstruct what a video would have shown with fairly good precision. I think it's just that

01:06:39.860 we're only on the horizon of being able to do things like that. But even still, you know, if you

01:06:45.520 measure 20 things in someone's blood, you can have a much better idea of what's going on,

01:06:51.640 what probably happened, than if you measure one thing in that blood. I should say 20 things in

01:06:57.780 the pathway, right? Yeah, yeah. And what you can get by measuring serially, even a few serial

01:07:05.380 measurements can be quite helpful. I mean, even just looking at something as, you know, simple,

01:07:10.000 I hate to say that, but as simple as an oral glucose tolerance test, you look at somebody's

01:07:14.820 fasting glucose and fasting insulin, you have some idea of what's going on, especially in extremes,

01:07:20.560 right? So a person who's fasting glucose is 70 milligrams per deciliter and their fasting insulin

01:07:26.260 is one. The probability that they're going to have postprandial hyperinsulinemia is low,

01:07:32.180 but it's not zero. Similarly, you look at somebody who's fasting glucose is 130 and their fasting

01:07:37.420 insulin is 30. The likelihood that there's not a train wreck there is also virtually nil.

01:07:45.040 But if you're willing to sample 30, 60, 90, and 120 minutes after a glucose challenge,

01:07:50.800 you can develop a very interesting kinetic pathway using just two or three measurements.

01:07:57.460 You know, I often get asked, where will machine learning wreak the most havoc in medicine? And

01:08:02.900 my intuition is most likely radiology is the most obvious place for machine learning to,

01:08:09.400 I mean, wreak havoc is the wrong word, but displace human, you know, ability. I've often

01:08:15.320 thought the ICU would be the second most valuable place just based on the reams of data that are coming

01:08:20.700 out. But I've never thought of this particular question, right? Which is something as seemingly

01:08:27.500 straightforward as looking at a bunch of biochemical metabolites and precursors and intermediaries.

01:08:34.240 There may be a very interesting opportunity here for machine learning to also start to differentiate,

01:08:39.040 but you know, this question of flux, I'm always asking myself that question when I look at a blood

01:08:43.340 test, which is, this is a static test. Can I infer the movement, the velocity or the derivative,

01:08:50.880 the time derivative of this molecule or that molecule? So maybe, maybe that is an interesting

01:08:55.700 place for machine learning to start to play a role because I do suspect it will do a better job than

01:09:00.060 me. Yeah. And what we, what we do have, taking it back to the fatty liver, what we do have is

01:09:05.980 not, you'll never see this in your day-to-day clinical life, but what we do have is studies

01:09:11.840 where we look at labeled tracers. And that's what shows that in a random sample of Nash people,

01:09:16.760 you have a 75% decrease in ApoB secretion. It doesn't matter what the ApoB in the blood is.

01:09:21.240 It's, you'd like to know why it's higher, but you know that it's not because it's coming out

01:09:26.060 of the liver at a higher rate. It's not secretion. It's a great point, right? It can be longer

01:09:29.620 residence time at the VLDL, the LDL, the, yeah, that's such a, such a great point. Okay. So

01:09:35.740 speaking of tracers, which just prompted me to think of another thing I wanted to talk with you

01:09:39.140 about, let's talk about the most sought after, discussed, asked about supplement on the market

01:09:46.960 today, which are NAD precursors. I know, I know you've got some feelings on this. I have pretty,

01:09:53.760 I have pretty strong feelings on this topic too. I'm trying to think how we can frame this. So

01:09:58.860 let's take a step back. Well, let's, let me do this for the listener who is contemplating whether

01:10:04.300 or not they should turn the podcast off now or not, because you barely hung on to the biochemistry

01:10:09.140 of choline and fatty liver disease. Most people have heard of NR, nicotinamide riboside,

01:10:15.940 NAD as the sort of fountain of youth. And if you've listened to other podcasts I've done,

01:10:22.700 specifically when I spoke with David Sinclair, we talked a lot about sirtuins and the necessity of

01:10:28.580 NAD as a substrate to sirtuins. What many of you have also probably heard of is there are a couple

01:10:35.920 of companies out there that are making a very popular supplement. One of them is called Elysium.

01:10:40.540 They make a supplement called Basis. The other is called Chromadex. They make a supplement. I

01:10:44.800 think it's called True Niagen. Am I right on that? Yeah. I believe that Basis takes nicotinamide

01:10:51.980 riboside, combines it with terastilbene, which is a sirtuin activator, and that is their product.

01:11:00.420 And my recollection is that the True Niagen folks are just giving nicotinamide riboside. I don't

01:11:06.640 know if they have a sirtuin activator in there, but I could be wrong, and it's probably not relevant

01:11:10.080 unless you know the answer. They don't. Okay. All right. So the thinking goes as follows.

01:11:16.720 We have this little thing in our cells called mitochondria, and they have all these little

01:11:21.600 complexes, and these complexes are basically used to generate reducing agents that move electrons to

01:11:26.180 one side of a double membrane, and it builds up a gradient, and then that gradient allows us to

01:11:31.240 make a bunch of ATP, and that whole process is called oxidative phosphorylation. The first of

01:11:35.340 these complexes turns NAD into NADH, and, oh, pardon me, NADH to NAD. So as we age, it has been

01:11:47.140 postulated and maybe even observed. I don't know if it's been truly observed inside the mitochondria.

01:11:51.480 Maybe it has. That the ratio of NAD to NADH goes down, and if that's happening, then you have

01:11:57.820 presumably less NAD. With NAD being an important substrate for sirtuins, which do many things but

01:12:04.320 primarily repair DNA damage, it would seem that we would want more NAD. Okay. You also have NAD

01:12:11.260 depletion because the sirtuins and the PARPs, which is the other class of enzymes that are using NAD

01:12:16.620 for the purpose of protecting DNA and telomeres and all the things that are postulated to be

01:12:22.740 important to aging and longevity, they consume the NAD molecule. They're consuming the NAD. That's

01:12:27.260 right. Yeah, absolutely. Which I think are two totally different things. Correct. And there's

01:12:31.480 another great example of it's hard to know why NAD levels might be low. Is it low because of high

01:12:38.500 consumption and high demand, or is it low because of low production? Well, so if you have, if you're

01:12:43.240 looking at the ratio of NAD to NADH, then I think that being in the overfed state is the thing that's

01:12:48.640 the problem. If you're talking about NAD amount levels dropping, then you're looking at consumption

01:12:55.060 by the PARPs and sirtuins that are consuming it for the purpose of repairing damage. Yeah.

01:13:02.180 So in an ideal world, if you could wave a magic wand, you would presumably want more NAD inside your

01:13:07.520 mitochondria. Tell us why that magic wand doesn't exist. Why can't you just eat NAD and land the

01:13:13.180 words? I wouldn't say it doesn't exist, but it's questionable how powerful of a wand this is.

01:13:19.960 So there's niacin. These are all forms that collectively, we call all this stuff niacin in

01:13:25.220 the diet. It's vitamin B3. And in the foods that we eat, we primarily get niacin in the form of

01:13:30.480 nicotinic acid from plant foods. We primarily get it in the form of nicotinamide from animal foods.

01:13:36.620 Like if we eat steak, a lot of the niacin that's in the steak is going to be in the form of NAD

01:13:42.580 or NADPH that is in those cells. But all of that has to be digested. And what we're absorbing in

01:13:52.200 the intestines is either nicotinic acid or nicotinamide. My guess is if you take a nicotinamide

01:13:58.700 riboside supplement, you are absorbing the NR intact. And if you take a nicotinamide mononucleotide

01:14:05.640 supplement, NMN, you are probably digesting that down to NR or nicotinamide and absorbing them.

01:14:11.660 But we are definitely not absorbing NADH or NAD in the intestines. So when we're eating food,

01:14:20.180 once we go into the enterocyte, we have nicotinic acid primarily being converted over to nicotinamide.

01:14:29.140 And the intestinal cell tries to turn that into NAD. But whatever the intestinal cell doesn't turn

01:14:35.120 into NAD itself, it passes on to the liver. So you're going through the portal vein. Now you have

01:14:40.540 maybe some nicotinic acid left, depending on how much you ate. You have some nicotinamide in there.

01:14:46.760 In theory, if you took a nicotinamide riboside supplement, you got some nicotinamide riboside in

01:14:51.020 there. Then it goes into the liver. And the liver is the main site that's really metabolizing

01:14:55.460 all these forms for the entire body. And what the liver is going to do is it's going to try to

01:15:00.840 convert as much of those forms into NAD as possible, not even just for itself, but because

01:15:07.060 it's going to hold a reserve of NAD for the rest of the body. And then almost everything that comes

01:15:14.260 out of the liver into the circulation is nicotinamide. So the overwhelming thing that

01:15:20.740 gets niacin out of the liver to any other tissue is nicotinamide. That's the transport form.

01:15:28.220 And then those tissues will convert that into NAD. So what we definitely don't see is we don't see

01:15:35.320 NAD and NADH being transported in the blood. There's some there, but it's not a physiological

01:15:41.120 transport way to get something from one place to another. If you take a nicotinamide riboside

01:15:46.480 supplement, you will get some nicotinamide riboside in the blood. Animal experiments

01:15:50.820 suggest that there are trace amounts of that that will get into certain cells like muscle cells

01:15:56.500 and be converted into NAD. But there are a physiologically meaningless amount of the NAD

01:16:03.520 that wound up in that muscle cell from taking that supplement. Overwhelmingly, if you're talking

01:16:08.280 about a tissue other than the liver, what's happening is that supplement gets converted into

01:16:13.320 nicotinamide, reaches the other tissues as nicotinamide, and increases tissue NAD by that

01:16:20.240 tissue taking the nicotinamide and making the NAD. But the first pass effect is pretty significant,

01:16:25.300 right? So let's talk about... First the pass effect is basically complete. We'll come back to NMN

01:16:29.640 in a moment, but let's just talk about NR. NR becomes NMN, becomes NAD, I believe, in the cycle.

01:16:37.320 If you take NR, yeah. Yeah. So if you take NR, which is the two most popular supplements on the

01:16:43.240 market with respect to this particular pathway, the liver is basically, to your point, taking all of

01:16:50.880 that NR and making NAD, correct? Yes. So do we have a sense of how much NAD actually makes its way

01:16:59.500 into even the cytoplasm of a cell that is non-hepatic in that situation? NAD that came from

01:17:06.180 where? That is derived ultimately from the NR that you ingested. From the liver? Yes. Oh, we know exactly

01:17:12.020 what happens. The liver turns that into nicotinamide and secretes it for the rest of the cells.

01:17:16.060 How much? Like a meaningful amount? As a portion?

01:17:19.480 Yeah. Well, or just... Well, I don't know off the top of my head the amount, but what I can tell you

01:17:24.900 is that for all intents and purposes, all of the NAD that is in any of your cells that are not the liver,

01:17:32.280 well, actually, I should say maybe 5% the kidney synthesized from protein. But aside from that 5%

01:17:39.760 in the kidney, pretty much every molecule of NAD is ultimately derived from circulating nicotinamide

01:17:46.680 that the liver put out. So in other words, it's not the case that NR needs to be brought into a cell

01:17:53.480 to be turned into NAD. It's that nicotinamide gets into a cell to be turned into NAD.

01:17:59.360 It's not even needs to, it can, right? Because NAD, to my knowledge, does not go from plasma

01:18:04.740 into cell, but it's hard to know if... It does. It does. It just might be that you don't have

01:18:09.280 enough in the plasma to justify the... Well, you do if you're injecting it.

01:18:13.320 Oh, so this is interesting. Okay. I want to come back. I'm going to park that because I want to

01:18:15.960 let you finish, but I'm going to come back to that. So nicotinamide is the physiological circulating

01:18:20.980 form of niacin that all cells will use to make nicotinamide. I mean, excuse me, that all cells will

01:18:28.560 use to make NAD. Minor exceptions are about five. We can make some niacin from tryptophan and about

01:18:36.040 95% of that happens in the liver, 5% happens in the kidney. So there is some, some tiny bit of this

01:18:44.660 that the kidney is making its own, but overwhelmingly with that tiny exception, a tissue is getting NAD

01:18:53.160 because it took nicotinamide out of the blood that the liver made from its store of NAD.

01:18:58.280 Now, let me expose my ignorance in biochemistry and my forgetfulness. Nicotinamide is charged or not?

01:19:04.260 I know NAD is, but... No, nicotinamide is not charged.

01:19:07.360 Okay. So nicotinamide makes its way into a cell through an active or passive transporter.

01:19:11.780 Active transporter, I believe. I would need to check that.

01:19:14.480 That's okay. We'll figure all that out. Once nicotinamide is in the cell, how does it combine

01:19:20.380 with adenosine, et cetera, to become NAD? It goes through two steps that are ATP dependent.

01:19:26.920 It gets converted to nicotinamide mononucleotide, and then it gets converted into NAD. A portion of

01:19:31.900 the NMN, nicotinamide mononucleotide, a portion of that becomes NR, and then gets, comes back to NMN.

01:19:38.800 And I don't know exactly why, but I think it's like a pressure release valve. So if you're trying

01:19:43.520 to hold on to the nicotinamide and get it to NAD more than the rate at which you can make the NAD,

01:19:49.820 you might convert some to NR to kind of hold on to it.

01:19:52.820 Got it.

01:19:53.040 And then it comes back and ultimately-

01:19:54.640 Wait, to NR or to NMN?

01:19:55.740 No, to NR.

01:19:56.360 To NR. Okay.

01:19:57.380 So you have nicotinamide, you go up to NMN, you go up to NAD. You can go from NMN over to NR,

01:20:04.160 but you have to go back over from NR to NMN to get to NAD.

01:20:07.960 Yep. And I think of it as a cycle.

01:20:09.980 Way easier to look at this in a picture.

01:20:11.520 Yeah, yeah. The picture that I have in my mind is NAD going to NAM to NMN as a cycle

01:20:17.520 with NR being a pop-off of NMN.

01:20:20.420 Okay, yeah. So what you're talking about is in the case of NAD consuming enzymes like

01:20:26.360 sirtuins and PARPs that are using NAD for DNA repair and all those things we were talking about

01:20:31.380 before, what they do when they consume the NAD is they release nicotinamide.

01:20:36.900 So imagine you're a muscle cell. You took originally, to get every molecule of NAD you

01:20:44.680 have, originally you took some nicotinamide in from the blood, but then you did things with it.

01:20:49.940 Some of those things were what you were talking about with oxidative phosphorylation.

01:20:53.700 You don't consume NAD in that process. You just cycle it back and forth. You use it over and over

01:20:57.300 and over and over again. But some of the things that you did were with the sirtuins and PARPs that

01:21:01.840 are engaging in protection. And those enzymes will consume the NAD to generate nicotinamide.

01:21:10.480 The big problem here is that nicotinamide is an inhibitor of all those enzymes through negative

01:21:19.120 feedback loop. So you have to, have to, have to, have to, have to do something with the nicotinamide

01:21:25.360 very fast, or you need to methylate it, bring it back to the earlier discussion and pee it out.

01:21:33.140 So nicotinamide is circulating as the circulating form in the blood, but intracellularly, you don't

01:21:39.060 let it hang out there. You do something with it, right? So you take in the nicotinamide and you

01:21:43.840 either make NAD or you get rid of it. Yeah. Actually, I didn't even realize one could have

01:21:49.100 free nicotinamide inside a cell, which I guess you're basically saying that that's, but only momentarily.

01:21:54.260 Momentarily. Yeah. Yeah. Yeah. But it doesn't hang out there in that form. No, it doesn't.

01:21:58.360 Okay. So now let's go back to the question that I'm still trying to wrap my mind around,

01:22:02.320 which is if I give you a gram of nicotinamide riboside, you're saying none of that NR is basically

01:22:09.980 going to leave the liver. Instead, just nicotinamide is leaving the liver. It is found in the blood. So

01:22:15.220 there's clearly, there is some nicotinamide riboside in the blood and we don't have the data in humans,

01:22:22.580 but we do have the data in mice. Isn't this what Josh Rabinowitz did in that tracer study over the

01:22:27.780 summer? That's exactly what I'm referring to. So in his paper, what he showed was that there is a

01:22:34.340 little bit of nicotinamide riboside that gets into the blood, that there's a little bit that gets into

01:22:38.200 some of the cells, not others. So for example, it can't cross the brain at all. It's fairly decent

01:22:43.420 at getting into muscle if it's there. There's not a lot there, but what is there can get into the

01:22:47.960 muscle and there is a little bit that gets turned into NAD. But the nice thing about his study was

01:22:53.940 he was, the way that he designed the tracers was they could see... Yeah, you want to be able to

01:22:59.020 separate the nicotinamide from the nicotinamide riboside, right? Well, they could see even at the

01:23:04.320 level of detail as like what was the history of this molecule before it became NAD. So they could

01:23:10.760 differentiate inside the muscle cell, they could differentiate the pool of NAD that the muscle

01:23:15.680 made from nicotinamide riboside. They could, from the pool that it made from nicotinamide,

01:23:20.820 even from the pool that it went through the cycle and then back, right? So they had extremely fine

01:23:27.420 detail. And what they showed was that there's a little bit of nicotinamide riboside that makes

01:23:30.860 it into the muscle intact. I pulled up the graph to try to see the amount and they have to blow up

01:23:37.680 that part of the bar graph to show you what that tiny trace looks like. It's basically practically

01:23:43.060 meaningless. Now, what they also showed in their papers, and also in the same group published one

01:23:48.960 in 2016, what they also showed was that you do increase NAD in the muscle a lot when you supplement

01:23:56.500 with the nicotinamide riboside. But it all comes from nicotinamide that the liver had made and

01:24:02.460 circulated in the blood. And let's just make the math easy. You take one mole of NR orally,

01:24:07.540 we've already acknowledged that the amount of NR that escapes the blood is so small you need a

01:24:13.780 magnifying glass to see it. So it's a picomole or something. How many moles of nicotinamide make

01:24:20.680 their way into the cell? Again, I'm sort of directionally speaking. But order of magnitude,

01:24:27.640 is it more of it or like the majority of it does? Or how much loss is there outside of the first pass

01:24:35.160 effect? Is there an inefficiency? Well, what are you calling loss? Are you calling increasing hepatic

01:24:40.020 NAD loss? Or are you calling... I'll call loss anything that prevents the actual nicotinamide

01:24:47.620 from making it into the cell. I don't know off the top of my head what those numbers would be.

01:24:54.080 But I can come back, I'll come back to the human data that Chromadex has published, that the Chromadex

01:25:00.580 people have published on that point. But what I can say about the physiology is that there's a lot

01:25:06.180 that doesn't get into any particular cell that isn't actually lost. And I think this is a really

01:25:11.020 important point because in the Rabinowitz group in 2016, they had another paper where they actually,

01:25:18.680 when you're listening to this, I mean, what's your thought right now? Would NR be more effective

01:25:22.880 than nicotinamide eating it? That's a good question. My intuition would have been NMN would

01:25:30.620 have been the best precursor if you could get it around the liver. So as a thought experiment, like

01:25:36.720 SL, like under, you know, sublingual or intravenous NMN would have been my intuition as the best way to

01:25:44.800 increase intracellular NAD. If you didn't have that choice, if nicotinamide is the circulating form

01:25:52.240 that's getting into the muscle, would you think that an NR is just generating nicotinamide that

01:25:56.860 gets into the muscle? Yeah, I think based on what you're saying, I would now say nicotinamide per

01:26:01.060 se would be a better substrate. Right, but it's not. And in the two, that's what I would think too.

01:26:06.280 I love how you walked me down that path. Well, no, because as I'm saying this, it sounds like

01:26:10.480 why on earth would you take anything other than nicotinamide? It's just going to make nicotinamide

01:26:15.700 anyway. And I think this gets back to your waste point too. In the 2016 paper that the Rabinowitz

01:26:21.880 group put out, they showed that, and this was a minor portion of their study, so they didn't have

01:26:27.460 anywhere near as much data as they had on the NR, but they showed that they got a much less NAD

01:26:33.840 response in the muscle with oral nicotinamide than they did with NR, even though they also showed

01:26:41.360 with very elegant tracers that it all got there as nicotinamide. Let me make sure I understood what

01:26:46.760 you said. You give oral nicotinamide, and you are now asking the question, how much of it goes to

01:26:53.680 the liver? How much of it leaves the liver also is nicotinamide and makes it to the muscle?

01:26:57.280 They didn't have all that data on the oral nicotinamide.

01:26:59.080 Okay, so they skipped that step, but they're going from—

01:27:00.840 They're asking the question, in the muscle, our goal is to increase NAD in the muscle.

01:27:04.240 Yep.

01:27:05.120 Is it more effective to give oral NR, or is it more effective to give oral nicotinamide?

01:27:10.500 And a minute ago, I would have said oral nicotinamide would make more sense, but you're

01:27:16.680 saying the opposite.

01:27:17.480 They showed the opposite, yeah. Here's the rationale that—now, this is kind of my synthesis.

01:27:22.260 But did the 2018 paper shed light on that now? Because now they had a tracer.

01:27:27.040 They had tracers in the 2016 paper, too.

01:27:30.540 But they couldn't see how much tyrosine in the liver was being—

01:27:33.500 Yeah, there was much more kinetic flux data in the 2018 paper. That clarified—you know,

01:27:41.080 if you had them on to talk about it, I'm sure you'd get better responses about the details.

01:27:44.900 I've tried to get Josh on a hundred times, and Josh and I are friends because we went

01:27:48.080 to medical school together, and I just can't get him to hop on a train and come up here.

01:27:52.360 So Josh, if you're listening to this, please just come up so we can talk about this.

01:27:56.640 Yeah, I'll just say what I learned about this paper, right? Because I read the paper,

01:27:59.200 I took notes, I synthesized them, I did my own podcast about this. So I think I have

01:28:03.480 pretty decent understanding of that paper, but I'm sure there's details that I forgot. So

01:28:07.080 what I learned from that paper is a bunch of things. Like, for example, I know now that the

01:28:12.800 average NAD molecule turns over every eight hours, you consume an NAD molecule in most tissues,

01:28:17.860 but it's every two hours in the liver, things like that. I know that the spleen and the small

01:28:22.700 intestine consume 40 times more NAD than the muscle and the fat does. So there's a bunch of data in

01:28:27.600 that paper, but there's not infinite data about the proportion that went in each compartment everywhere.

01:28:33.480 Back to the point about why is it more effective to take the NR? What I, and this is what I think

01:28:38.680 is going on, what I think is the most sensible rationale that makes sense of this. So in the

01:28:44.660 liver, you imagine that the NR, the nicotinamide, nicotinic acid, whatever it was you ate gets into

01:28:50.960 the liver. Think about that cycle that we talked about before. So we go from nicotinamide and we go up

01:28:58.860 to NMN, we go up to NAD. If we consume the NAD with sirtuins and PARPs, we come back to nicotinamide

01:29:05.400 and having that nicotinamide around is a liability because it's going to inhibit all the repair

01:29:11.420 enzymes. So we either want to make NAD out of it or we want to get rid of it. If you eat oral

01:29:17.040 nicotinamide and you absorb oral nicotinamide into the liver and the liver gets it, that oral

01:29:23.540 nicotinamide is immediately a liability before it ever becomes NAD because it can inhibit all those

01:29:31.300 enzymes, the sirtuins and the PARPs. So the liver has these two, has a bifurcation of what can it do

01:29:38.740 with this? It can methylate it to get rid of it and pee it into the urine or it can make NAD. If you

01:29:45.320 take NR, then you go into NMN, you have to make NAD before you ever generate nicotinamide and expose

01:29:54.800 it to the detoxification process. What I believe is happening, and I think this is backed up by the

01:30:00.880 animal data, is nicotinamide riboside is a superior way to increase hepatic NAD because when it gets to

01:30:10.380 the liver, it can't be immediately detoxified. It's not immediately a threat to the sirtuins and PARPs,

01:30:15.620 and it can only make NAD before it does anything else. And again, this is a flux thing, right? It's

01:30:23.220 not like the liver says, okay, cells, tell me what our balance of NAD and NMN is on Friday, and on

01:30:30.100 Saturday, I'll make a decision about how much to empty into the urine. This is an immediate thing

01:30:35.860 that's happening right now. The liver says, oh, got two choices. I either detoxify this or I do

01:30:40.220 something useful with it. And so if you're presenting it with that thing that's a threat

01:30:44.940 and it has to make that decision, it can only make so much NAD at once at one time, then you're

01:30:50.120 going to have much more waste in the detoxification pathway than if you put the thing in that has to

01:30:56.620 make NAD, that is not a threat when it makes NAD, and that has to actually generate NAD to ever be

01:31:03.240 exposed to the detoxification pathway. So you have to appreciate the central role of the liver in

01:31:10.140 controlling the flux throughout the entire body. The liver's not just making NAD for itself.

01:31:15.860 It's making NAD because it carries all of the reserves for the rest of the body as NAD. So the

01:31:23.620 liver doesn't just have NAD that's immediately being used in respiration and is immediately being

01:31:28.520 used in sirtuins and parps. It has a reserve pool of NAD that it holds onto for the specific purpose

01:31:34.800 of a slow release of nicotinamide to the rest of the tissues that they will take up. And then they

01:31:41.440 will have the immediate decision to either detoxify it or make NAD. But if the liver can hold on safely

01:31:47.920 to the NAD and have a better ability to release nicotinamide on an as-needed basis and a continuous

01:31:55.860 basis at a rate that the other tissues can take up and do something useful with, then because you got

01:32:03.600 a superior way of increasing hepatic NAD, you got a better continuous flux that was optimized

01:32:11.020 of nicotinamide to reach the other tissues so they can make NAD.

01:32:14.620 Yeah. So in that sense, it's actually sort of parallels glucose, right? In the sense that

01:32:19.760 we have to maintain about 5 grams of glucose in our bloodstream at all times. So if you have 10

01:32:27.140 grams of glucose in your bloodstream, you have diabetes, you've got huge problems, you're going

01:32:31.640 to go blind and get your toes cut off. But not if you have 100 grams in your liver.

01:32:35.060 Exactly. But 5 grams is perfect. And by the way, if you have 2 grams, you die. It's an amazing problem

01:32:41.480 where the liver is constantly titrating. So you're basically drawing a parallel that says it's probably

01:32:47.080 doing the same thing, holding on to NAD. So in this analogy, NAD is to glycogen what glucose is to

01:32:56.540 nicotinamide. Yeah. Is that a fair analogy? It's a fair analogy, except there's a probably much

01:33:03.820 larger percentage of the hepatic NAD pool that's actually being, like proportionally, they're

01:33:08.540 different. But yeah, in principle, I think that's a good analogy. So let's see if we can go deeper on

01:33:14.180 that analogy. There are a lot of people out there who, in fact, I have a friend who came to me a year

01:33:20.200 ago and he said, I've got the greatest idea. I'm going to open up an IV NAD clinic and we're going

01:33:26.060 to do NAD and ketamine. So we'll give you ketamine to get rid of your depression and NAD to make you

01:33:31.500 live longer. And I said, well, I'm interested in the ketamine because I do think that's a super

01:33:36.480 interesting molecule for recalcitrant depression. At least a year ago, I said, my understanding is

01:33:42.100 giving intravenous NAD is not going to increase intracellular or certainly mitochondrial NAD.

01:33:49.540 And I don't know that that makes sense. Though I've got many friends who have done IV NAD and

01:33:54.020 they all say the same thing. It's the worst feeling in the world. Oh, I know why it's the

01:33:57.720 worst feeling in the world. Say why. We need to come back and say, what is the role of free NAD

01:34:03.560 that's found extracellularly? I can guess what the role is. What I can tell you is that one of the

01:34:10.260 things it does is it activates granulocytes to cause vasodilation and a massively ramped up

01:34:17.020 inflammatory response. So not unlike niacin? No, it's very different from niacin.

01:34:21.000 But niacin has a very similar response, doesn't it, at very high levels?

01:34:24.120 Well, yeah, but biochemically what's happening is totally different.

01:34:26.500 Oh, it is. Okay. So why is niacin causing a flush? So it's not the same as NAD's flush.

01:34:30.960 So nicotinic acid is, specifically nicotinic acid, activates the nicotinic acid receptor.

01:34:40.460 And that is present on a bunch of immune cells that are responsible for the flushing response.

01:34:46.120 But not necessarily granulocytes.

01:34:48.200 Yeah. So NAD is acting on, it's a different receptor. And, you know, I don't know, maybe it's

01:34:55.100 more, it might be more similar than I was leading on. It's a different receptor,

01:34:59.220 but maybe the results are similar. I've never injected, I've never had the flushing response

01:35:03.600 and I've never injected NAD. It probably is fair to say that they're similar in their results

01:35:08.980 and that there are some similarities biochemically, but it's not the same biochemical mechanism.

01:35:13.720 So if you do inject this NAD, what is it now? You've bypassed the liver and it's sitting there

01:35:21.700 in the plasma. What's clearly happening based on the anecdotal reports of the immediate response to

01:35:28.340 that is that they're, that they are causing an inflammatory response. What is not clear is

01:35:33.240 the kinetics of where that NAD is going, but there's, there is definitely papers that I was

01:35:38.440 able to find showing that there are a variety of mammalian cell types that do have the ability

01:35:44.700 to take that NAD into the cells. But I look at this from the perspective of what is the normal

01:35:50.580 physiology? I don't, I don't really want to know what can happen. First, I want to know what's

01:35:54.600 supposed to happen. Then I'll build a theory about what I should do based on that, right?

01:35:59.220 For people who are not injecting it, how does NAD get out of this cell in the first place?

01:36:03.700 Well, the details aren't worked out, but it appears to be that NAD, extracellular NAD is from dead

01:36:09.460 cells, from dying cells, and maybe from cells that are undergoing some sort of stress response

01:36:14.380 and are secreting it to some degree to reflect their energy status.

01:36:20.820 You mean as a signal?

01:36:21.740 As a signal.

01:36:22.760 Interesting.

01:36:23.360 Oh, yeah. I think it's very clear.

01:36:24.920 You think it can be a signaling molecule as well?

01:36:27.200 I think it's very clear that there, if there is any role for extracellular NAD,

01:36:31.380 it is as a signaling molecule. And I think it's almost certain that there is a role for

01:36:35.200 extracellular NAD as a signaling molecule because there are fairly decently characterized enzymes

01:36:42.660 that consume NAD that are found extracellularly. There's a whole class of extracellular NAD

01:36:48.640 consuming enzymes. So if NAD is not ever supposed to be outside of the cell, why would it be

01:36:53.460 there? And it's like, well, what do those enzymes do? They break it down to use it as

01:36:58.380 a signaling molecule. So it has to be the case that extracellular NAD is primarily a signaling

01:37:03.860 function. And so it's definitely not a normal way of transporting NAD from tissue to tissue.

01:37:09.720 What the signal means, I think, will probably be debated if enough people care for a long time

01:37:16.760 to come. So I have no idea exactly how to simplify and state what it means. But it's very clear that

01:37:22.380 it's a signaling molecule. So when I look at NAD injection, I'm like, my idea is I'm going to

01:37:30.700 transport this thing. And that's definitely not the way you transport that thing. And my body's idea

01:37:36.100 is that that's a signal that means something about what's happening that is definitely not happening

01:37:41.820 when I... Right. Because you're amplifying potentially a signal that's negative.

01:37:48.080 Yeah. And, you know, maybe that has good consequences because maybe it's some kind of

01:37:51.740 rescue signal. Maybe a stressed cell puts NAD out and says, come help me or come get rid of me

01:37:59.140 because I suck. Yeah. But if that's the case, gosh, when you took a mother load of NAD

01:38:05.140 in the plasma, what are you supposed to go after every cell? I mean, how would you even differentiate

01:38:10.620 where that signal, where that alarm is coming from? Well, that's why I would never do that. But I think

01:38:14.220 if I'm trying to look... If I'm trying to explain why are people experiencing... Reporting benefits from

01:38:19.700 it, either it's placebo or it's doing something. And if it's not just placebo, my guess is that it's

01:38:27.020 probably... It's probably having some signaling effect that is by virtue of luck doing something

01:38:33.940 that the person is reporting is beneficial. But I'm not going to do that because I have no idea

01:38:38.020 exactly what that signal means. So what's your take then, you know, kind of going back to where

01:38:43.060 we were a moment ago, which is doing what seems to be much more commonly done, which is taking oral

01:38:48.960 NR or oral NMN? Okay. So oral NMN, I would bet money that it's not absorbed intact.

01:38:57.020 And that's because NMN has a charged phosphate group on it. And generally charged phosphates

01:39:06.160 cannot cross cells. And so they're hydrolyzed. And even if it were to be true that there were

01:39:13.760 transporters in the intestines that could take NMN up intact, it probably still would not be absorbed

01:39:19.320 intact because the phosphatases in the small intestine that cleave the phosphates off of everything

01:39:25.780 that all the molecules in the food you eat do so non-specifically to all of the molecules in the

01:39:32.920 food you eat. So for example, riboflavin, when you consume riboflavin 5-phosphate, I'm quite certain

01:39:39.380 that none of it is absorbed intact. Were that because there were a specific riboflavin 5-phosphate

01:39:46.260 phosphatase that just cleaved that phosphate, then I would say, well, I don't know about niacin.

01:39:51.500 I need to look for the phosphatase. But that's not the case. What is the case is that in a normally

01:39:55.820 functioning small intestine, you have this overabundance of nonspecific phosphatases that

01:40:01.780 just cleave the phosphates off of everything that you're eating. And that's because even though there

01:40:07.840 might be some exceptions to the rule, perhaps, the overwhelming rule is that it's really difficult

01:40:12.600 to carry charged phosphates across the intestines, across cell membranes in general. So I doubt that

01:40:20.900 the NMN gets in there intact. And I think that if anything, maybe it gets cleaved to NR and the NR

01:40:26.360 does. I believe the NR gets intact because that's what the Rabinowitz group's paper showed, that it was

01:40:31.800 getting into the liver as NR. And because it makes sense because NR doesn't have a charged phosphate on

01:40:37.080 it. Okay, so we can simplify it and say, let's just limit our discussion to NR. And let's just say now we're

01:40:42.880 taking super physiologic doses of NR, which would be, you know, what's prescribed in these supplements,

01:40:48.380 sort of 500 to 1000 milligrams daily. We, you know, using our glycogen, somewhat oversimplified analogy,

01:40:55.620 we're now increasing our hepatic reservoir of nicotinamide that we can slow drip out when it's demanded,

01:41:03.120 because that's going to be the better way to do it. Right. So there's promise based on the animal

01:41:09.000 experiments, although there are in the human trials that they've done, they haven't showed any benefit

01:41:13.320 of doing this at all. Now what you mentioned Brenner, I mean, you didn't mention him by name,

01:41:17.020 but you mentioned Chromadex. Tell me a little bit about their work. I've looked at a couple of their

01:41:20.500 human studies. And they've done a couple of studies where they've characterized the metabolites

01:41:25.260 that are produced when you take oral NR. And they've done a couple studies where they tried to look for

01:41:31.500 some benefits and didn't really find any. So there's no benefits on glucose metabolism. There's

01:41:36.300 no benefits on lipid metabolism. Now, were they doing these as kinetic studies or were they actually

01:41:41.100 trying to look for phenotypic improvement? In the first study, they just took one person and they

01:41:48.700 extensively characterized all the metabolites that were produced in three different compartments.

01:41:54.560 But then there were two, and I don't know if this is comprehensive, but in the studies that I looked at,

01:41:59.020 there were two other studies where they were measuring in different populations, they were

01:42:05.700 measuring things that you would relate to health, like glucose and triglycerides.

01:42:10.700 And you're saying those things did not improve.

01:42:13.200 Yeah. In fact, there's in one of the papers, I believe it was the triglycerides went up a little

01:42:17.580 bit and the potassium, the serum potassium went down a little bit. I mean, nothing that was that you

01:42:22.040 wouldn't conclude anything from it, but it didn't, it didn't look like it was doing anything good.

01:42:26.260 Now I want to make a couple of caveats here because these have been pretty short studies

01:42:30.980 and my suspicion is... And furthermore, they're not even measuring what we really care about,

01:42:36.180 right? I also don't think they're measuring like what you would necessarily expect to see,

01:42:40.560 which I think is harder to measure. So if you think about it, think about the Rabinowitz paper,

01:42:45.360 which showed that the, the turnover of NAD is, and this is in mice, but it's all we have right now.

01:42:51.560 The turnover of NAD in the small intestine is 40 times what it is in muscle.

01:42:58.180 Explain that to me. I mean, that is so counterintuitive.

01:43:00.800 Think about it from the opposite perspective. So we're thinking about life extension or health

01:43:05.040 span extension with super physiological doses of NR. Think about the opposite case of pellagra,

01:43:10.580 which is niacin deficiency. Where do you see that? You see the, if you're an optimist,

01:43:15.800 you say the three Ds of dermatitis, diarrhea, and dementia. If you're a pessimist, you say the four

01:43:22.640 Ds and you include death. And in the brain, what's going on is NAD is actually generating

01:43:29.400 molecules that are directly involved in immediate neurotransmitter production.

01:43:34.340 So I think that's why you see brain effects in pellagra. But overwhelmingly, if you exclude the brain,

01:43:40.860 the two tissues where you are seeing the most dramatic effect are the two tissues that are

01:43:46.480 outside of the body.

01:43:48.460 Okay. So it's interesting. I was going to say, is it because they're outside the body or is it

01:43:51.540 because of the rapid turnover?

01:43:53.080 I think part of the rapid turnover is because they're outside the body. I mean, think about,

01:43:56.900 think about the quality control inside your body compared to outside your body, right? Like think

01:44:02.220 about once we cross the intestinal barrier, ideally we have incredible control over what passes that

01:44:08.140 barrier. But we have no control with what it encounters.

01:44:12.940 Think about what goes into the toilet. Like, would we want that inside our body in the number

01:44:16.780 two, right? So I think part of the reason that NAD is so, and I'm guessing in their paper,

01:44:22.740 if they had characterized it in the skin, that it would be high, but they didn't.

01:44:26.200 So what do we know about what causes pellagra? Well, when you're out in the sun, you're always

01:44:31.500 experiencing DNA damage from that sunlight. You're always repairing it. So in the skin, you have this

01:44:35.980 very incredibly high NAD turnover in the skin because even things that you normally think are

01:44:42.420 benign, like just going outdoors is actually causing damage that, that you are repairing always.

01:44:48.120 And so when you have the skin having a very high need to constantly repair itself, and then you take

01:44:54.400 away its ability to do that, then suddenly you see this manifestation in the skin. In the gut,

01:44:59.360 what's happening is, I think part of it is that it's so energy intensive to maintain the cell

01:45:04.280 turnover in the gut. But it's also the case that just like the skin, the gut is exposed to so many

01:45:09.440 insults of just total lack of quality control over the things that come inside it. And my suspicion

01:45:18.060 is that where you would be likely to see benefits of increasing tissue NAD over the short timeframe is

01:45:26.080 going to be in those tissues with the highest turnover. Like you're going to look at skin quality

01:45:30.220 and small intestinal health, both of which are very hard to wrap my mind around how you would design

01:45:38.140 the ideal study compared to measuring glucose and insulin and triglycerides and lipoproteins,

01:45:44.740 right? Like you know exactly what you would measure for metabolic syndrome. I would have to sit down and

01:45:49.440 really think about how I'm going to measure someone's skin quality or their small intestinal health.

01:45:53.380 Over the long term, what you would expect is increased genomic stability,

01:45:57.420 decreased accumulation of DNA damage, and increased telomere length, none of which have been measured.

01:46:05.140 But also why, I mean, I could certainly think of ways that those things could not be preserved,

01:46:11.040 even in the absence of gut and skin dysfunction. In other words, you could still see epigenetic damage

01:46:22.140 in the presence of perfect gut and skin barrier, right?

01:46:29.320 You're just saying you would expect to see less of it if you created a better barrier?

01:46:35.020 You were saying that over the long haul, you would expect to see less epigenetic change.

01:46:40.660 Oh, okay. Let me clarify. The point that I'm trying to make is that if you're talking about a 12-week

01:46:45.140 or 16-week time period, I don't think you're going to see any results unless you're looking for specific things.

01:46:51.420 Oh, you're saying based on the non-external benefits. In other words, to understand what it's doing

01:46:58.560 inside all of the other cells in the body, you're going to need a much longer time horizon.

01:47:01.480 Exactly.

01:47:01.840 Okay, I got it.

01:47:02.620 Exactly. And so we basically don't have much data because we have these several-week-long studies in humans.

01:47:10.940 And if we're going to look at things going on inside the body, besides those tissues with super high turnover,

01:47:16.520 I think we're going to have to look at longer studies that have more relevant endpoints.

01:47:21.620 So let's talk about it from the standpoint of harm.

01:47:23.820 Okay, yeah.

01:47:24.560 Because the other way we can think about this is if you're cost insensitive,

01:47:29.860 what's the downside in spending $100 a month, which is about what you're going to spend

01:47:33.520 to take the party dose of these compounds?

01:47:37.400 So I think the potential risk is that you're sapping your methyl group supply.

01:47:43.120 And the reason is that, like we said before, part of this cycle is when you do generate nicotinamide,

01:47:51.200 you face the possibility that you have to methylate it and you have to pee out the methylated metabolite.

01:47:57.040 And then the question is, well, if you're taking 1,000 milligrams or 2,000 milligrams of NR a day,

01:48:03.800 which for the sake of putting some numbers on it, the RDA for niacin is around 15 milligrams.

01:48:10.840 So we're talking 100 times, right?

01:48:13.480 You are losing a lot of methyl groups.

01:48:15.480 And we know this in humans because the two papers that I found where they did measure methylated metabolites

01:48:21.600 of the nicotinamide riboside.

01:48:24.280 And what you see is that in urine and in blood cells,

01:48:29.060 you see incredible increase in the methylated metabolites of nicotinamide.

01:48:33.460 But wait, so wouldn't a quick and dirty test be homocysteine should go up, for example,

01:48:41.400 in a patient taking NR if they're losing methyl donors?

01:48:45.240 No, I don't think so.

01:48:46.500 I don't think that would be the most sensitive thing.

01:48:48.000 And I think we will eventually see a paper showing that that's not true because I've

01:48:52.380 heard Brenner on a podcast say that he measured homocysteine and he measured S-adenazylmethionine

01:48:58.380 levels in the blood and showed that it doesn't have any effect.

01:49:01.260 So I didn't see that paper published yet, but I think it will come out.

01:49:05.140 You're saying that you're always able to methylate folate even, like we just prioritize the methylation

01:49:12.640 of folate high enough that even if we're losing methylation capacity to NR, we're still going

01:49:19.220 to preserve it at the folate level, I guess.

01:49:21.080 So yeah, I don't know if we, we might need to back up and talk about the methylation cycle

01:49:26.440 to make this clear, but you tell me.

01:49:28.660 So the most sensitive thing that changes when you have a change in the methyl group supply

01:49:33.800 is your creatine synthesis.

01:49:35.740 Interesting.

01:49:36.720 So I want to come back to that.

01:49:38.160 If we jump to methylation, can we remember to come back to finish this?

01:49:41.500 Because we do need to talk about MTHFR and COMT and all of our other friends.

01:49:46.260 If we're going to do, I think it would be much easier to talk about the methylation of

01:49:50.300 NR and what you would want to measure in a study to test that.

01:49:53.520 I think it would be way easier to do that after.

01:49:55.720 All right.

01:49:56.080 So now we're going to, hopefully, I'm going to write this down.

01:49:58.880 We're going to come back to this.

01:50:00.080 Let's talk about that five-letter acronym that pretty much everybody's heard of by now,

01:50:04.800 but nobody really knows what the heck it is.

01:50:07.100 What is an MTHFR gene and what is an MTHFR mutation and should anyone care?

01:50:14.520 All right.

01:50:15.120 So as we had said before, a methyl group is a one carbon unit and the methylation cycle

01:50:20.860 uses the amino acid methionine to donate that one carbon to dozens of different things.

01:50:28.380 So what we do there is we activate methionine to S-adenazylmethionine using ATP.

01:50:35.540 And S-adenazylmethionine is the universal methyl donor.

01:50:39.020 So no matter what we're talking about synthesizing, what we're talking about regulating, it is always

01:50:43.380 S-adenazylmethionine that donates that one carbon, that methyl group.

01:50:47.940 It becomes, through two steps, it becomes homocysteine, which is the inevitable byproduct of using it.

01:50:54.480 And once we have homocysteine, we have two choices.

01:51:00.020 We can either get rid of the homocysteine if we have an abundance of methyl groups,

01:51:04.620 or if we don't have enough methyl groups, we will recycle the homocysteine back to methionine.

01:51:09.080 There's two ways to do that.

01:51:10.920 One is that folate, which is vitamin B9, can take a methyl group from amino acid metabolism

01:51:19.640 and can pass it on to B12, B12 passes it on to homocysteine, homocysteine regenerates

01:51:26.260 methionine.

01:51:27.840 Or choline can be oxidized to beta-in, which can be then the methyl donor to recycle homocysteine

01:51:36.800 to methionine.

01:51:37.980 Those two pathways are equivalent.

01:51:40.140 In the average person, they're probably 50-50, but it's going to depend on their dietary intake.

01:51:44.840 To your question about MTHFR, the MTHFR enzyme is one of the enzymes that is involved in

01:51:54.080 constructing the methyl group that came from amino acid metabolism that went on to the folate

01:51:59.260 molecule.

01:52:00.480 And that's how folate passed the methyl group on to B12 and then on to homocysteine to recycle

01:52:06.460 methionine.

01:52:07.700 There's a lot of people going around saying, I have MTHFR.

01:52:11.220 Well, we all have MTHFR.

01:52:13.840 I have ATP.

01:52:16.240 Exactly.

01:52:17.240 It's not just misleading because we all have MTHFR.

01:52:19.820 It's also misleading because there's actually, if you look at the two common polymorphisms,

01:52:25.840 which are gene variants in the MTHFR gene, they are so spread out in the population that

01:52:31.700 what you actually see is a gradient of MTHFR activity that's fairly even spread across

01:52:36.080 the population.

01:52:36.740 So you could basically divide the population into quintiles of MTHFR activity and you'd

01:52:42.820 see it wouldn't be exactly 20, 20, 20, 20, 20, but it would be fairly close to that.

01:52:47.860 So if you have limited ability to use folate for methylation, there are several things happen

01:52:55.300 that happen.

01:52:56.000 The first is that you use up more choline.

01:52:59.920 And you do that because you suck at using folate and you have no problem using choline.

01:53:06.960 So you basically say, I'm not that good at using this pathway.

01:53:10.320 I'm going to use the alternative.

01:53:11.700 And that nutritionally, that makes the choline requirement go up.

01:53:14.220 At the very beginning of this podcast, I said that I'd seen some studies where some people

01:53:18.260 need 1,200 milligrams of choline.

01:53:20.200 That's the people with the worst MTHFR activity.

01:53:22.960 What happens is there were two different populations that were studied and exactly what

01:53:26.860 happened to their choline metabolism was different in each population.

01:53:29.820 But the commonality was...

01:53:31.160 And the worst function is, remind me, it's ACCC, or TTCC, which SNPs would be the quote

01:53:38.280 unquote worst?

01:53:38.860 The worst case for MTHFR is the C677T homozygous.

01:53:45.740 Homozygous A or...

01:53:47.340 Homozygous for T instead of C.

01:53:50.460 Yeah, yeah, yeah.

01:53:50.840 So it's the TT.

01:53:52.020 And then on the A1298C, it's like the...

01:53:56.760 Yeah, for the A1298C, that one is less significant than the C677T, but you can have both of them.

01:54:05.460 So in the best case, you have neither of them.

01:54:08.040 That's like 10% or 15% of the population.

01:54:10.220 But the next step up to have a little hit is to have...

01:54:13.520 You're basically a CA or a CT, and you're functionally pretty close to normal.

01:54:18.540 I like the way you described it, actually, which is think of it in quintiles.

01:54:22.700 Yeah.

01:54:23.060 And I would even say it's less than quintiles because to your point, in my experience,

01:54:27.760 I only see maybe 10% of people that are wild type in both.

01:54:33.320 That's pretty freaking rare.

01:54:35.100 I mean, I would be surprised if it's 10%.

01:54:36.440 No, that's exactly what it is.

01:54:36.880 You'd be surprised if it's 10%.

01:54:38.000 No, it's not...

01:54:38.800 Right.

01:54:39.040 It's not exactly quintiles.

01:54:40.360 But it depends what population you look at, too.

01:54:42.920 It's going to vary.

01:54:43.660 But it's...

01:54:44.240 Basically, there's a little bit in each category.

01:54:47.400 Yeah, yeah, yeah.

01:54:47.800 And there's not a category that has...

01:54:49.800 And it even has a large minority of the people in it.

01:54:52.080 That's right.

01:54:52.420 It's not even like APOE where you can say, well, the two twos are basically unheard of

01:54:57.160 and the three threes, the wild type.

01:54:58.360 Yeah, there's no one that's unheard of.

01:54:59.600 Yeah, yeah.

01:55:00.080 And it's almost like I don't really know what the wild type really is.

01:55:03.760 Yeah.

01:55:05.080 I think it's misleading to call it even wild type and to say, you have the mutation.

01:55:09.860 Yes.

01:55:10.220 It's really like there's a spectrum that's even more convincing than gender, right?

01:55:15.480 In this case, it's like a very even, literal even spread.

01:55:19.320 Like, no one could make a case for binarism in MTHFR.

01:55:23.180 So let's, for the sake of being overly simplistic, which is not necessarily a good thing, but

01:55:28.640 to illustrate this point, let's compare the best methylators to the worst methylators,

01:55:34.340 meaning let's take the top and bottom quintiles of MTHFR function to now illustrate the point

01:55:39.940 you were making a moment ago before I interrupted.

01:55:42.260 Right.

01:55:42.640 And that's, I mean, that's really where we have most of our data from.

01:55:45.380 So if you compare the best, and I don't even want to call them the best methylators.

01:55:48.040 I know, I know, I know.

01:55:49.320 Because they're not bad methylators.

01:55:50.960 They're pretty good because they're using up their choline to do it.

01:55:54.540 So if you compare the people with the best methylfolate status compared to the people

01:55:58.520 with the worst methylfolate status, the people who have bad methylfolate status are the people

01:56:03.240 who are doubling up the amount of choline that they're blowing through for the cycle.

01:56:07.260 Now that said, Chris, it's hard to deny.

01:56:10.640 I mean, I'm getting to the point where one of my favorite games to play, because I just

01:56:13.580 love to play games with myself when I'm reviewing a patient's labs.

01:56:16.600 I like to predict a homocysteine based on an MTHFR.

01:56:21.820 And there's an undeniable correlation, which is not to say I can always predict it.

01:56:25.740 But when I look at your MTHFR status, the lower you are in your capacity to efficiently do so,

01:56:33.900 the higher your homocysteine is, all things equal.

01:56:37.080 Now, wouldn't we expect that if they're truly as efficient at methylation, even using choline,

01:56:43.160 shouldn't they be able to compensate for that?

01:56:46.060 Okay.

01:56:46.240 So, right.

01:56:47.020 I think I probably misspoke when I said they're just as good methylators because they're using

01:56:53.940 choline.

01:56:55.000 Yeah.

01:56:55.340 It's a compensatory response.

01:56:57.220 But the thing is, what you see in the literature, at least, is that studies that can show a statistically

01:57:03.860 significant rise in homocysteine, it's generally limited to the people who are in the worst case

01:57:11.660 scenario.

01:57:12.700 What's interesting that I think no one is talking about, and I didn't even realize this until

01:57:18.040 last week, is that if you subdivide those people by their riboflavin status, all the people who have

01:57:26.660 the MTHFR genotype that look bad, that have high homocysteine, have bad riboflavin status.

01:57:34.620 And the thing that lowers MTHFR activity with those polymorphisms is that MTHFR is a riboflavin

01:57:43.160 dependent enzyme, which is vitamin B2, and it has a lower affinity for the riboflavin as a cofactor.

01:57:50.020 And so you need better riboflavin status to optimize your MTHFR.

01:57:53.040 This is so counterintuitive, you know, because the thing that we find clinically that is the

01:57:57.800 best hammer is B6.

01:58:00.160 Because you're not thinking about optimizing the MTHFR activity, you're thinking about getting

01:58:04.180 rid of the homocysteine.

01:58:05.040 That's right.

01:58:05.620 Right.

01:58:06.040 And do you think that's the wrong way to think about it clinically?

01:58:08.940 Yeah, I think it's the wrong way to think about it.

01:58:10.280 I think it's too simplistic.

01:58:11.700 But if someone has high homocysteine and goes away with B6 supplementation, that person probably

01:58:15.820 needed a high B6.

01:58:17.120 We should talk a little bit more about how this pathway is regulated.

01:58:20.400 So...

01:58:20.760 I have a feeling this is going to be a set of show notes.

01:58:23.040 So it's going to have some really awesome diagrams.

01:58:26.200 I actually sent Bob 30 slides on this.

01:58:29.040 Awesome.

01:58:29.580 Thank you.

01:58:30.060 Okay.

01:58:30.300 So let's say that you eat a steak.

01:58:33.500 There are some good things and bad things about that.

01:58:35.420 One thing is that you have a bunch of methionine in there.

01:58:39.060 And you can use that methionine for methylation.

01:58:42.120 One of the negative aspects of that is that if you have this boatload of methionine that comes

01:58:47.280 in, you're going to generate a boatload of homocysteine.

01:58:50.320 And you also don't have the problem of needing to recycle that homocysteine because you've got

01:58:55.580 a boatload of methionine coming in.

01:58:56.940 In fact, it's probably dripping into the liver and you can probably predict that if you have

01:59:00.700 a lot right now, you're going to have even more coming in 10 minutes from now and even

01:59:04.000 more coming in 10 minutes from now.

01:59:05.620 So what do you do?

01:59:07.040 You totally shut down MTHFR.

01:59:09.560 You totally shut down the enzyme that uses choline.

01:59:13.300 So you're not recycling it anymore.

01:59:15.240 And then you flip on this other enzyme that's not usually active that gets rid of the homocysteine

01:59:20.960 by just breaking it down.

01:59:23.980 And then on top of that, you want to get rid of the extra methyl groups and you turn on

01:59:29.440 this other enzyme that is going to use the amino acid glycine as a buffer.

01:59:34.200 And then that glycine is going to, if it can, hold onto the methyl group for later use.

01:59:40.040 But if you methylate too much of that glycine, you wind up peeing it out.

01:59:43.300 So in this context, what the B6 is doing is it's activating the enzyme that kicked on

01:59:50.440 when you ate the steak that helped you break down the homocysteine.

01:59:54.360 So if a person has high homocysteine, it goes down.

01:59:57.560 The part of the point that I want to make here is that they're not different parallel

02:00:01.100 ways to do the same thing.

02:00:02.960 Your MTHFR shuts down in the fed state if you ate protein.

02:00:08.100 The enzyme that uses B6...

02:00:09.500 And when you say protein, do you mean specifically methionine or do other amino acids?

02:00:12.720 Well, there's methionine in every protein.

02:00:14.740 There's more methionine in eggs.

02:00:16.900 There's more methionine in meat compared to plant foods.

02:00:20.560 But there's enough methionine that if you just eat a meal that has a reasonable amount

02:00:24.260 of protein, you're going in this direction.

02:00:27.020 So take the opposite situation, which is the amino acid that falls most quickly when you

02:00:32.300 fast is methionine.

02:00:33.580 We don't preserve methionine the way, for example, we preserve branch chain amino acids

02:00:37.600 in a non-fed state.

02:00:39.520 So three days into a fast, you should have very high MTHFR activity?

02:00:44.340 Yes.

02:00:45.480 How this ties back to the patients with the B6 is that it's proof of concept that the B6

02:00:52.720 worked, that the problem you addressed was not MTHFR.

02:00:56.560 That means that part of their high homocysteine, it was a result of fed state homocysteine that

02:01:04.220 should have been broken down using the vitamin B6 that wasn't broken down because they didn't

02:01:08.660 have enough B6.

02:01:10.240 The B6 is working because those people need more B6.

02:01:13.300 So this is actually very interesting, Chris.

02:01:15.320 So it's almost like we should define how much methylfolate and how much methyl B12 one needs,

02:01:22.100 even in the presence of MTHFR mutations that are quote unquote bad, and if they're still

02:01:28.920 not lowering homocysteine, flogging them with more of that is not the answer.

02:01:33.120 You have to move to TMG or B6 or something like that.

02:01:36.800 So, you know, I think the typical supplement we would give a patient would have 400 micrograms

02:01:41.220 of methylfolate and maybe 800 micrograms of methyl B12.

02:01:46.300 Does that seem like even overkill, reasonable, more than sufficient?

02:01:49.980 I think it's reasonable.

02:01:50.980 Yeah.

02:01:51.120 And if that's not fixing the problem, you got to look elsewhere.

02:01:54.760 Well, you're not going to fix MTHFR with methylfolate.

02:01:57.160 No, no, sorry.

02:01:57.640 If that's not fixing the homocysteine, you haven't identified what the deficit is.

02:02:02.020 Yes.

02:02:02.740 But we went down this direction because we were talking about is homocysteine a good

02:02:08.460 indicator of whether you're messing up your methylation.

02:02:10.360 So I think homocysteine, yes, there's data saying maybe the homocysteine is a problem in

02:02:16.520 and of itself because it causes oxidative stress and might contribute to cardiovascular disease.

02:02:20.440 But mostly it's, but it's also just a marker that things aren't working right in that cycle.

02:02:27.900 But it's not the only thing that goes wrong in that cycle.

02:02:30.800 You have other alterations.

02:02:32.520 So for example, what I had said at the very beginning of this about some people need 900

02:02:37.540 to 1,200 milligrams of choline, that's because people with, and you're not going to fix this

02:02:42.960 by fixing homocysteine.

02:02:44.320 People who have low MTHFR activity are doubling the amount of choline that they blow through.

02:02:49.980 And they have problems that are a result of not having enough choline that have nothing

02:02:54.700 to do with homocysteine whatsoever that need to be fixed by putting more choline into the

02:02:59.540 system.

02:03:00.640 So I'm not telling you that their homocysteine is going to go down when you put the choline

02:03:04.620 in.

02:03:04.960 Maybe it will because choline is a methyl donor.

02:03:07.660 But what I'm telling you is that the data indicate that those people have a higher choline

02:03:11.560 requirement.

02:03:12.340 And the way that you address that is by consuming enough choline.

02:03:15.120 Is there then a relationship between MTHFR and propensity to fatty liver disease, given

02:03:21.880 that a subset of patients are going to be burning through choline quicker and therefore have

02:03:25.760 less choline to do its job in the liver?

02:03:29.160 I would expect that that could be the case.

02:03:31.800 Off the top of my head, I don't know of data on that.

02:03:35.280 What I do-

02:03:35.960 Hopefully there's a graduate student listening to this who's going to pick, because that'd

02:03:39.500 be a really interesting and elegant experiment that demonstrates that.

02:03:43.200 What I do know there's data on is showing that 900 to 1200 milligrams of choline will

02:03:48.840 do two things.

02:03:50.240 One, it will minimize markers of oxidative DNA damage.

02:03:54.360 And I'm not even sure what that mechanism is.

02:03:56.040 And the second thing that it does is it just, it brings choline utilization markers back down

02:04:03.180 to what you would find in someone who didn't have the MTHFR polymorphism.

02:04:08.160 And it comes back to everything that we said before about the relative fluxes, right?

02:04:12.140 So if someone's using up their choline more for that process, I wouldn't necessarily expect

02:04:17.000 them to have fatty liver, but I would expect them to have a higher probability of developing

02:04:20.380 it if you put the other conditions in.

02:04:22.580 And again, just going back to what you said earlier, you would generally recommend people

02:04:26.100 supplement with phosphatidylcholine versus choline?

02:04:28.860 I would prefer food.

02:04:30.000 And if you're going to do a supplement, I would prefer phosphatidylcholine over a choline

02:04:34.500 salt.

02:04:34.840 So where does COMT fit into all of this?

02:04:38.800 Because it's another enzyme.

02:04:41.400 It's involved in the catabolism of catecholamines.

02:04:45.320 Talk a little bit about that.

02:04:47.200 So part of moving beyond homocysteine, one whole side of this equation is what are you

02:04:54.200 methylating, right?

02:04:55.260 Because homocysteine is a byproduct of the methylation cycle.

02:04:57.580 What you're methylating is 90% of it is to synthesize creatine and to synthesize phosphatidylcholine.

02:05:06.200 And then the other 10% is a gradient of a handful of things that are fairly sensitive to methyl

02:05:12.240 group supply and a lot of things that aren't.

02:05:15.320 If you look at the next most sensitive thing to creatine synthesis, it's dopamine.

02:05:20.580 And COMT is the enzyme that methylates dopamine.

02:05:23.440 Basically, what it does is it modifies dopamine metabolism in a way where if you methylate

02:05:31.000 more dopamine, you are mentally more flexible.

02:05:34.500 And if you methylate less dopamine, you are mentally more stable.

02:05:38.920 And if you're in the middle of that, it could just be a variation of your personality.

02:05:44.080 But as you start to get to the ends of that spectrum, you start to get into the possibility

02:05:49.700 of psychiatric disorders that could be a result of being in the extremes.

02:05:54.480 But in the middle of that spectrum, they talk about the warrior phenotype and the worrier

02:05:58.940 phenotype.

02:05:59.980 So the person who's the worrier, W-A-R, is the person who has a higher rate of methylating

02:06:07.220 dopamine.

02:06:08.080 It's more mentally flexible.

02:06:09.680 And that's the person that picks the battle, faces it, picks the battle, faces it, defeats,

02:06:14.360 and just moves from one thing to the next.

02:06:16.160 The worrier gets stuck on things that they're worrying about.

02:06:19.880 But you look at, just like MTHFR activity, you look at COMT activity, and it's a perfect

02:06:25.620 spread.

02:06:26.320 There aren't as many different types.

02:06:27.920 It's basically like 50% of people are in the middle, 25% are on one end, 25% are on the

02:06:32.400 other end.

02:06:33.120 Why is it spread like that?

02:06:34.300 Because there's a trade-off.

02:06:36.240 And so I think the worrier, worrier phenotype is a bad way to talk about it because actually

02:06:40.920 the people with the so-called worriers, the so-called people who worry, W-O, W-O.

02:06:46.980 Yeah, it's hard to pronounce that exactly right.

02:06:49.740 So the people who have a low rate of methylation, they're also better at doing a lot of things

02:06:54.920 that require sustained focus.

02:06:56.760 So better at academics.

02:06:58.700 There was a recent study that came out that showed that competitive swimmers who are the

02:07:03.380 low methylation phenotype get better results.

02:07:06.760 They appear to do better competitively.

02:07:08.560 And there was another study in elderly people that found that if you do an exercise intervention,

02:07:13.880 the people with the low COMT phenotype are more likely to do more exercise because you

02:07:20.600 told them to.

02:07:21.500 So these are people where things get stuck in their mind.

02:07:24.980 And things getting stuck in your mind is great if it's the right thing.

02:07:29.200 So you are predisposed to worry more because if you get an anxiety-producing thought or a

02:07:35.240 depression-inducing thought in your mind, it gets stuck there more.

02:07:37.420 But also, if you're going to focus on work that needs to be done, if you're going to focus

02:07:42.080 on goals, you might be better at that because you've put the right thing in your mind and

02:07:48.300 you had a better ability to make it stick there.

02:07:51.080 Is the other group, the warrior group, more susceptible to addiction?

02:07:55.980 Yeah.

02:07:56.640 So if you look at the associations of the genotypes with different psychiatric diseases, the ones

02:08:04.660 that are most clearly related to impulsivity or getting stuck on stuff are the ones that seem

02:08:12.460 to be most consistently correlated.

02:08:13.920 So obsessive compulsive disorder is associated with the low methylation phenotype, whereas

02:08:19.900 substance abuse and ADHD are associated with the high methylation phenotype.

02:08:27.660 Then when you start looking at other psychiatric disorders, you start to get into a lot of noisy

02:08:32.140 data when you look at depression and anxiety and panic disorder and things like that.

02:08:36.260 But just taking the extremes, how strong are those hazard ratios?

02:08:39.280 Off the top of my head, I don't know.

02:08:42.260 Directionally, are they meaningful?

02:08:43.880 Are we talking about hazard ratios of four and five?

02:08:46.180 Or are we talking about like 1.17s?

02:08:48.380 I genuinely don't remember.

02:08:49.940 I can put a meta-analysis of this in the show notes that I have.

02:08:53.100 Okay.

02:08:53.480 That would be great.

02:08:54.500 I mean, because this is one of those things that only once have I ever been asked about

02:08:59.060 this.

02:08:59.300 And I didn't know the answer, of course.

02:09:00.380 But one of my patients asked me to go back and look through his genetic data to look at

02:09:07.380 which SNPs he had for COMT specifically because of this question.

02:09:12.340 Oh, yeah.

02:09:12.660 I don't think it has much diagnostic utility.

02:09:14.980 I find it interesting from creating a theoretical model of how this stuff works.

02:09:21.700 And I think part of the reason some of the data is so noisy about like, let's say, things

02:09:26.640 in the middle like depression and anxiety, which they do correlate.

02:09:29.460 And there are studies that show it one way, but it's just very noisy data.

02:09:33.340 I think part of the reason it's so noisy is that it's not really about the genetics.

02:09:37.480 Like, you see really strong associations with genetics when you have a monogenic disease.

02:09:41.700 Of which there's like 73, right?

02:09:44.200 I mean, there's virtually none.

02:09:45.560 It's not the norm, right?

02:09:46.900 When you're talking about this, it's like COMT is not a gene for a mental state.

02:09:51.280 Right.

02:09:51.720 It's a gene that has a partial influence on the stickiness of your mind.

02:09:56.940 And the way that COMT methylates dopamine is with all the methyl donors.

02:10:01.100 So nutrition is going to play directly into that.

02:10:04.160 And so your COMT genotype isn't even going to tell you the rate at which you're methylating

02:10:09.080 dopamine.

02:10:09.860 It's going to tell you the rate at which you could methylate dopamine given a certain

02:10:13.620 supply of methyl donors.

02:10:14.940 You've put a lot of time into this, Chris, and we'll make sure we link to this.

02:10:18.180 But you've basically done probably a better job than anyone I know of at codifying the,

02:10:23.800 if you have this mutation, this would be a great dietary strategy.

02:10:27.260 It would take us another 12 hours to go through all of them.

02:10:31.160 Let's touch on three of them.

02:10:32.780 You pick, but it seems to me that the COMT, MTHFR would be an interesting one to at least

02:10:37.160 start with.

02:10:37.800 Sure.

02:10:38.240 So MTHFR, I think what you want to do is, number one, you want to get between 900 and

02:10:43.240 1200 milligrams of choline a day.

02:10:45.760 That is the nutrition.

02:10:46.280 And your preference, clearly, sorry to interrupt.

02:10:48.120 Phosphatylcholine.

02:10:48.700 But get it from your food.

02:10:49.840 Get it from food.

02:10:50.080 Like if you can eat enough eggs and, you know, okay.

02:10:53.520 So there's that.

02:10:54.800 And that is, that has the most data backing it out of everything else that I'm going to

02:10:59.240 say.

02:10:59.900 But supplementation with creatine makes a lot of sense because 45% of your methyl demand

02:11:05.640 is to synthesize creatine.

02:11:07.440 And just to put this in perspective for the listener, when people think creatine, these

02:11:11.780 days we think about creatine monohydrate versus creatine phosphate, which used to be the

02:11:16.020 sub, the supplement monohydrate.

02:11:17.700 Right.

02:11:17.840 So creatine monohydrate is something that most people take for exercise.

02:11:22.160 They take about five grams a day.

02:11:24.180 Back when I was in high school, we used to load it.

02:11:26.420 We would take 20 grams a day for five days, then five grams, and we'd cycle on and off.

02:11:31.160 You're probably not old enough to have been in that meathead phase.

02:11:34.180 But the most recent literature I saw.

02:11:36.000 No, I did that.

02:11:38.220 The tradition lived on.

02:11:40.460 It's still on the label.

02:11:42.040 Is it really?

02:11:42.620 Yeah.

02:11:43.560 Although the most recent literature I've seen said just monohydrate five grams a day.

02:11:47.400 There's plenty.

02:11:48.280 But again, for most people, we think of that as creatine as a phosphate donor.

02:11:53.940 And in certain types of exercise, i.e. the most high intensity, so weight training, for example,

02:12:00.040 that burst is really a phosphate donation from creatine.

02:12:04.260 It's not an ATP-driven process.

02:12:06.000 I actually wasn't really aware of the role of choline in synthesizing creatine.

02:12:12.400 It's a role of methylation in synthesizing creatine.

02:12:17.660 And so that whole cycle, whether you're taking the methyl groups from choline or you're taking

02:12:21.460 the methyl groups from folate, what you do when you synthesize creatine is you start with

02:12:26.320 guanidinoacetate, which you make from the protein in your diet, and then you methylate

02:12:29.780 it, and that makes creatine.

02:12:31.320 So literally, creatine is the only thing that is super sensitive to the methyl group supply.

02:12:37.380 So you ate that steak, you synthesized creatine.

02:12:41.280 Five hours later, you're synthesizing nowhere near as much creatine.

02:12:44.700 And the whole system is designed—

02:12:46.340 So creatine tracks much more closely to, say, methionine than leucine.

02:12:51.100 Yeah, because the rationale is that some things are so essential to the body that you don't

02:12:59.240 want them to ever change with the methyl group supply.

02:13:02.560 So DNA methylation for gene expression, you don't want to regulate thousands of genes because

02:13:09.700 you ate a steak and you had a bunch of extra methyl groups.

02:13:12.280 You want to control that for totally different reasons.

02:13:15.120 So that's designed to almost never change.

02:13:17.600 Then there are other things that have to be fairly acutely stable, like your dopamine

02:13:23.600 and other neurotransmitters.

02:13:25.160 You don't want that to go up meth like twice as much because you ate, right?

02:13:30.020 But your creatine, you—average person has 120 grams of creatine in their body, and they

02:13:35.180 lose two grams of creatine every day in the form of creatinine that they pee out in their

02:13:39.140 urine.

02:13:39.840 And so the whole point of creatine synthesis is to keep the accounts balanced.

02:13:43.680 So if you synthesized no creatine for an entire day, your creatine in your body is going from

02:13:51.200 120 grams to 118 grams.

02:13:53.500 It's like barely a dent.

02:13:55.540 So creatine is the ideal thing to vary with the methyl group supply because you can eat

02:14:00.640 a steak.

02:14:01.240 You can do all your creatine synthesis when you were—when you had enough methyl groups.

02:14:05.060 Then five hours later, you're in the fasted state, and you—you don't synthesize creatine

02:14:09.420 anymore.

02:14:09.840 It doesn't matter because it's not a neurotransmitter.

02:14:11.600 It's not doing an acute thing.

02:14:13.120 You just have to make sure that in 60 days from now, your creatine isn't zero.

02:14:18.620 It's still 120 grams in your body.

02:14:20.340 What determines the phosphorylation status of creatine?

02:14:23.100 Of that 120 grams, how much of it has an inorganic phosphate?

02:14:26.340 Oh, that's completely unrelated from the synthesis.

02:14:29.040 That's a matter of the energy state of the cell.

02:14:32.180 So just like ATP gets used when you use energy, creatine phosphate in when you're—so instead

02:14:38.860 of—

02:14:39.180 But do we have an enzyme—so the way that, you know, for example, like AMPK is a great

02:14:44.160 surrogate for ATP, ADP, AMP, right?

02:14:49.080 It really gives you a sense of the energetics.

02:14:51.580 Do we have similar enzymes that give us a sense of CP versus C, creatine phosphate versus

02:14:57.780 creatine?

02:14:58.520 I don't think there's an analogous enzyme, but there's a completely analogous energy

02:15:01.800 state.

02:15:02.120 So when you're exercising, for example, your ATP levels go down, your AMPK levels go

02:15:06.440 up, your creatine phosphate levels go down, your creatine levels go up.

02:15:10.040 When you recover, everything reverses.

02:15:13.480 So this is most studied in muscle.

02:15:16.340 But in an exercising muscle, if you do weightlifting to failure, you're going to see the creatine

02:15:21.760 phosphate go from about 100% down to about 40% at the point of failure.

02:15:26.300 And then you rest for five minutes and you're going to see most of it recovered.

02:15:30.900 So by that logic, I mean, the reason athletes like to use creatine is for increasing that

02:15:37.640 maximal performance or the duration of short maximal performance, right?

02:15:41.520 It's not going to have an impact on your ability to run a marathon, but it certainly

02:15:45.000 could have an impact—

02:15:45.600 I think it will have an impact on your ability to run a marathon.

02:15:48.260 You do?

02:15:48.760 Yeah.

02:15:49.380 Interesting.

02:15:50.340 Because creatine does things in muscle that are independent of that.

02:15:54.700 Independent of its phosphate donation.

02:15:56.560 Yeah.

02:15:56.900 So another thing that creatine does in muscle is that it hydrates the muscle more.

02:16:01.560 And so you literally have—

02:16:02.520 That's for sure.

02:16:03.460 Yeah.

02:16:03.620 I mean, that's a given just based on the amount of water that travels with it, right?

02:16:06.960 That is a direct factor in strength in a way that has nothing to do with the duration

02:16:10.160 of the exercise.

02:16:11.280 Yeah.

02:16:11.540 So for the listener, they should know that for, you know, anyone who's taking creatine knows

02:16:15.700 this, you're going to put on about four or five pounds, and it looks sort of like muscle.

02:16:20.520 I mean, it shows up in the right places, but a lot of it's just water moving to the

02:16:24.700 muscle, right?

02:16:25.240 That's water that directly increases your muscular strength.

02:16:28.420 Yeah.

02:16:28.940 Interesting.

02:16:29.460 So it's not just, you know, because a lot of guys will say, well, that's great because

02:16:32.480 I look bigger, but the reality of it is it's actually functional.

02:16:35.440 And they're stronger.

02:16:36.260 Yeah.

02:16:37.120 You know, you could get that amount of creatine if you just ate a few pounds of meat every

02:16:40.020 day.

02:16:40.920 And apparently there's a diet going around these days where people are doing just that, but I'm

02:16:45.260 not willing to commit to it.

02:16:46.620 The extent to which is important to kind of modify your diet around MTHFR really depends

02:16:51.560 on what problems are you facing and what goals do you have and to what degree do you want

02:16:58.260 to be anal about doing things that have theoretical payoff, right?

02:17:02.280 So I think that for someone who has either high homocysteine or they have psychiatric difficulties,

02:17:09.780 what you would expect from the low methylation state is for someone to be overly ruminating

02:17:15.720 on things.

02:17:16.820 And so if you feel like that's a problem for you and you feel like what you would typically

02:17:20.640 do to be psychologically healthy is an uphill battle because of your physiology, it might

02:17:24.500 be.

02:17:25.260 And so in that case, I think you would stick more to that protocol.

02:17:29.120 So obviously taking creatine, increasing your choline amount is the most data-backed thing.

02:17:34.700 But taking creatine makes a lot of sense because if you cut your methyl demand in half, then

02:17:40.500 it's probably going to matter half as much that you're not that good at methylating, right?

02:17:45.960 So you increase choline because that's the alternative methyl donor.

02:17:49.540 You put creatine into the system because that's decreasing the demand.

02:17:55.500 But there's another overlooked thing here, which is that methylfolate is, I don't know if you

02:18:02.260 want to go into the reasons why, but let me just state as a fact for faith acceptance,

02:18:06.480 methylfolate is the thing that controls whether you pee out glycine as a methyl buffer.

02:18:12.360 If your methylfolate level is low...

02:18:14.860 I'm closing my eyes because I'm now trying to figure out how trimethylglycine will fit

02:18:19.480 into this because I have an anecdote to share with you.

02:18:21.720 Well, trimethylglycine is beta-ene, which is a thing that you make from choline.

02:18:25.220 Finish your story.

02:18:25.900 I'm going to come back to this interesting anecdote because I'm looking forward to you explaining

02:18:29.140 to me why I observed this case, but keep going with this.

02:18:31.600 When your methylfolate level is low, your body thinks that you are in a state of methyl

02:18:38.000 abundance and that you need to methylate glycine and pee out the methyl groups on the glycine

02:18:42.220 into the urine.

02:18:44.480 And so you probably need more glycine as well.

02:18:48.240 No one's quantified it.

02:18:49.620 No one's actually shown that that's the case.

02:18:51.740 But what we know is very, very data-backed in terms of how does the system work?

02:18:57.740 And everything that we know about the system, how the system works, says if you have low

02:19:01.580 methylfolate levels, you'll lose glycine in the urine as methylated metabolites.

02:19:06.500 And so that means that you do want to put methylfolate in there because you want to try to have some

02:19:12.160 there to stop that.

02:19:13.620 But you probably need more glycine.

02:19:16.020 And what we know is that we can synthesize glycine, but the average person probably falls

02:19:21.860 short of their ability to synthesize glycine by 10 to 60 grams a day in terms of optimizing

02:19:27.120 collagen turnover in the skin and et cetera, et cetera, et cetera.

02:19:31.040 We also know that there are studies showing that people get better sleep if they take three to six

02:19:35.000 grams of glycine before bed at night.

02:19:37.240 People have better blood sugar if they take three to five grams of glycine with a meal.

02:19:40.880 So it's entirely reasonable that the average person could use more glycine.

02:19:46.560 And so I think it's entirely reasonable to say maybe throw some bone broth in here or throw

02:19:52.140 some collagen in here or some gelatin or some glycine.

02:19:56.620 Do you think it matters whether you're getting it in bone marrow, bone broth versus a supplement?

02:20:02.680 It would be in the bone broth.

02:20:06.260 And I think the big differences are between getting collagen in versus getting glycine powder.

02:20:13.680 So for collagen, and collagen is what you would get in bone broth, it's been shown to be better

02:20:20.900 at increasing collagen synthesis.

02:20:23.300 Is that, see, I've never understood why that's the case.

02:20:25.700 I've always kind of thought that that makes no sense because you eat a bunch of collagen.

02:20:29.460 What basically emerges from your gut is free amino acids.

02:20:34.300 No, there's some collagen peptides.

02:20:36.380 There's some dipeptides in there.

02:20:38.000 I mean, how robust are the data on that?

02:20:40.120 I don't know how robust they are.

02:20:41.620 I've actually told patients on a couple of occasions that have insisted that they take

02:20:44.980 their collagen that I just don't think it's helping them.

02:20:47.360 Well, I can believe that.

02:20:48.100 For the benefit of replacing their own collagen.

02:20:50.880 I've always been like, eh, I just don't see how that works.

02:20:53.740 I mean, the other things interest me more.

02:20:55.160 There's no good data showing that you will have less wrinkles.

02:20:59.460 If you take collagen, I've never heard of any data on bone health.

02:21:03.300 The other stuff's more interesting, frankly.

02:21:04.640 If you tell me that five grams of glycine in the form of collagen will produce better

02:21:09.200 glycemic control and better sleep, that's more interesting.

02:21:13.120 I'm pretty sure all of the blood sugar studies were done with glycine powder.

02:21:17.920 I might be wrong about that.

02:21:19.540 I know the sleep studies were done with glycine powder.

02:21:22.340 All I can think of off the top of my head for a study that was done, and this wasn't even

02:21:27.980 with collagen, it was with the gelatin, which I would assume would be the same.

02:21:31.480 His last name is Barr.

02:21:32.800 I forget his first name.

02:21:34.000 But there was a study that showed that before you exercise, if you take 15 grams of gelatin,

02:21:41.640 but not five grams with a little vitamin C, you will increase collagen synthesis in the

02:21:47.900 tendons.

02:21:49.240 And the rationale for the study, and actually, I didn't even look at this paper.

02:21:53.100 I just listened to an interview that he did about it.

02:21:55.640 The rationale was that in your muscle, your muscle's very metabolically active, very good

02:22:00.940 at taking things up when it wants to.

02:22:02.940 But the connective tissues in your joints are very dependent on you just pushing more blood

02:22:08.060 supply there.

02:22:08.680 And so when you exercise, you have the amino acids coming in before you exercised, and then

02:22:14.960 when you're exercising, there's an increased blood flow that gets the collagen peptides

02:22:20.120 into those tissues.

02:22:21.720 So part of my ideas here are speculation based on why this works.

02:22:25.860 And so I'm using the reasoning that we would expect those, like probably if you were measuring

02:22:31.900 plasma glycine levels in those people, you'd find lower levels of plasma glycine, and you'd

02:22:37.780 find higher levels of the methylated metabolites of glycine.

02:22:40.880 Probably if you looked in the urine, you'd find those things.

02:22:43.480 And so it makes logical sense to say that you may need more glycine, and so you can put

02:22:48.060 into your diet in these ways.

02:22:49.640 But ultimately, this is like...

02:22:51.160 What foods would be high enough in glycine if someone was sort of opposed to taking...

02:22:55.000 Skin and bones.

02:22:56.580 Yeah.

02:22:58.000 Including like chicken skin and things like that.

02:23:00.700 So bones are the highest, and skin is intermediate.

02:23:03.560 And bones, to your point, it's not the marrow, it's the broth you make from the bone.

02:23:08.120 Yeah, it's not the marrow, it's the broth, and it's dependent on the protein content.

02:23:11.700 So if you're making it homemade, you don't know exactly what the protein content is.

02:23:16.040 I would use the metric of whether it's well gelled.

02:23:18.860 If you assume you can trust the label, there are several bone broth products on the market

02:23:23.580 where they say they have 10 grams per cup.

02:23:26.460 And if they have...

02:23:27.100 And that's 10 grams of protein or 10 grams of glycine?

02:23:29.100 10 grams of protein, which should be about 3 grams of glycine.

02:23:31.960 Oh my God, so you've got to drink quite a bit of this stuff.

02:23:35.000 Well, a cup is 3 grams of glycine.

02:23:37.920 Yeah, but if you want to, you know, that's...

02:23:39.720 That's the bottom of your 3 to 5.

02:23:41.280 Yeah, you're going to drink that before bed every night and it might help you sleep, right?

02:23:44.860 In theory.

02:23:46.680 Okay, so now that we've walked through the methylation stuff,

02:23:50.900 I still want to go back to this NR, MN thing, because this is what got us down this path.

02:23:55.280 Right, so in the studies done by Brenner,

02:23:58.700 what we do know is that an enormous amount of this NR is getting methylated as nicotinamide.

02:24:09.060 I don't think it's possible to extract the data from those papers and say exactly how much

02:24:14.180 because they're in concentrations.

02:24:16.400 And when they're in urine, they're not in a 24-hour collection.

02:24:18.860 They're in spot urine.

02:24:19.540 Right.

02:24:19.740 I don't know exactly like what the up and down flux is over time.

02:24:22.380 But what I can say is that just as a rough calculation to get a sense of how much impact

02:24:30.360 you could have if the impact were maximal, for every 1,000 milligrams of nicotinamide that

02:24:37.340 you detoxify, you are in theory decreasing your synthesis of creatine by 500 milligrams.

02:24:44.120 So you're synthesizing two grams of creatine in a day.

02:24:49.040 So if you're taking 2,000 milligrams of nicotinamide riboside, if all of it were detoxified,

02:24:55.220 you'd be cutting your creatine synthesis in half.

02:24:57.860 But in theory, I mean, that means that you're going from 120 to 116 instead of 118, right?

02:25:02.560 In a day?

02:25:03.480 You're talking about whole body creatine stores.

02:25:05.840 I'm talking about synthesis.

02:25:06.660 You're talking about at the cellular level too.

02:25:09.360 First of all, no one's taking this for a day.

02:25:11.020 They're taking it every day if they're taking it, right?

02:25:12.600 And you don't need your creatine to go to zero before you have problems, right?

02:25:17.800 Like the bodybuilders and the athletes are taking creatine because they're hoping to maybe

02:25:22.020 increase their body stores by about 30%.

02:25:24.480 So just leveraging a little bit marginal increase creatine makes big results in your strength.

02:25:31.560 We should clarify that although 90% of creatine is in your muscles and although the most famous

02:25:37.460 reason to take creatine is to support your exercise performance, it's also been shown that five

02:25:43.780 grams of creatine a day improves depression in women with major depressive disorder.

02:25:48.320 And if you just look at the physiology of creatine, for God's sake, you're using it to make your

02:25:52.200 sperm swim and you're using it to pump acid into your stomach.

02:25:56.700 So creatine is important in all kinds of areas that you would not expect to think about it in.

02:26:03.400 So if one was going to take creatine, which I probably haven't taken since NAMM, you wouldn't

02:26:08.960 just take it during exercise.

02:26:10.580 Like if you wouldn't just take it on the days that you were lifting weights, which let's

02:26:13.620 say you were doing that three or four times a week, you would presumably want to take it

02:26:16.860 daily, take that five grams daily, correct?

02:26:19.780 Yeah.

02:26:20.260 I mean, I think on the whole, although you could say that it might be better if you take it

02:26:24.800 after exercise with a carbohydrate bolus, it might be better if you split it up into two

02:26:29.740 doses. On the whole, if you just take it every day and you take five grams a day and you just

02:26:34.440 always do that, you're eventually going to get to the-

02:26:37.680 Yeah, you'll hit that steady state.

02:26:38.460 You're going to hit, yeah, exactly. Yeah, it's something to take daily if you're doing that.

02:26:41.860 But let's steer away from the person who doesn't care at all about creatine supplementation.

02:26:47.580 They're not even thinking of that. What I'm thinking about is what would you want to do in

02:26:52.040 an NR study to show that you're not impacting methylation. So I expect that sometime rather

02:26:59.160 soon, we're going to see a paper coming out showing that it doesn't elevate homocysteine

02:27:03.320 and showing that it doesn't affect the S-adenosylmethionine in plasma. And my position is not that this

02:27:12.520 stuff is really dangerous. That's not my position at all. However, I've been exposed to anecdotes

02:27:17.880 of people who are taking this who experienced things that were really seesawing in their energy

02:27:24.980 levels and were really seesawing in their mental and emotional states that are anecdotes that could

02:27:31.420 be explained by a thousand other things. But to me, make it sound like, geez, this thing is really

02:27:37.080 sapping the methyl group supply. It's exactly what I would expect to happen in someone whose methyl

02:27:42.260 group supply is being sapped.

02:27:43.220 And would that person be better off supplementing with choline or creatine if they were going to

02:27:49.520 pick?

02:27:50.720 I would say take a lower dose of this stuff and match it with a methyl donor. Yeah, in theory,

02:27:58.520 you could do creatine. You'd have to test it, right? But my recommendation, I actually put out

02:28:03.280 the recommendation. I made a video about this. I said-

02:28:06.200 We'll link to it.

02:28:06.800 I said match it milligram for milligram with TMG, trimethylglycine.

02:28:10.300 Oh, that reminds me. I want to tell you about this anecdote. So we've got a patient who

02:28:13.880 you just couldn't get his homocysteine to budge. So on our lab scale, below like nine or less is

02:28:20.200 what would be normal. He's in the 13, 14, 15 region. On your standard dose of methylfolate,

02:28:26.640 methyl B12, nothing. Even doubling it, which always makes me a little uncomfortable, nothing.

02:28:32.560 Adding 50 milligrams of B6 three times a week, which strikes me as overkill, nothing. Going to B6,

02:28:39.100 50 milligrams daily, nothing. Add TMG, boom. Homocysteine falls by 50%. What was going on in

02:28:47.760 this guy?

02:28:49.160 Okay. So the fact that you added B6 and it did nothing indicates one of two things. Either

02:28:54.780 that guy's enzyme for getting rid of the homocysteine didn't work that well, or more probably,

02:29:00.300 this was not a fed state homocysteine issue, right? So the way these things work is you're

02:29:06.280 trying to use MTHFR or choline to remethylate homocysteine when you're in the fasted state

02:29:11.240 and you don't have a lot of methionine coming in. You stop doing that entirely and you start

02:29:15.740 trying to break down the homocysteine, getting rid of it when you're in the fed state.

02:29:19.880 So we don't know the flux. We didn't have the video. We just had a bunch of snapshots of this

02:29:24.620 guy's homocysteine. My guess is that unlike the guy whose homocysteine went down with the B6,

02:29:30.700 this guy, he had a recycling issue. He did not have a problem of disposing of the homocysteine

02:29:35.720 in the fed state. He had a problem of recycling in the fasted state. He just couldn't do it. And

02:29:40.540 he couldn't do it because his MTHFR just didn't work very well. And so only when you added the

02:29:46.100 trimethylglycine, which is the choline pathway. So when you use choline for methylation, what you do

02:29:50.840 is you convert it into trimethylglycine and that becomes the methyl donor that's the alternative.

02:29:56.580 I mean, it makes me wonder now if we just supplemented more choline, if we could have

02:29:59.680 got the same result.

02:30:00.740 Yeah, I'm sure you could have gotten the same result. The only possibility that would prevent

02:30:05.780 that would be if he had a problem with the enzyme that oxidizes choline to trimethylglycine.

02:30:10.660 I like that it all comes back to choline. We have four chickens at home and my kids named them. So

02:30:15.060 they have the funniest names. Two of them have pretty normal names. There's Sarah is one of them

02:30:20.400 and Bang Bang and Go-Go. You can almost tell which of my kids named them.

02:30:26.800 I feel like Sarah would feel left out.

02:30:28.620 Yeah, yeah, exactly. So little Bang Bang and Go-Go and Sarah and I can't even, I'm embarrassed

02:30:33.740 to admit on the spot, I forgot the name of the fourth chicken, but it's a totally normal name.

02:30:38.560 That's not funny because my daughter named Sarah and the normal one on my other guy. But now I feel

02:30:44.620 like even more indebted to these little guys. I mean, I've always loved eggs. And of course,

02:30:48.640 once you eat eggs that are like coming from the chickens that you're feeding, the leftover

02:30:52.740 vegetables on your table, like the yolks are so yellow, the eggs taste so good. It's very

02:30:59.260 interesting to see this connection between choline creatine methylation. I mean, this is complicated

02:31:07.120 stuff. And of course, the skeptic will take a step back and say, well, Chris, what if you're just

02:31:12.600 fixing a bunch of numbers? Like, yeah, you can make homocysteine go down and yeah, you can do this and you

02:31:17.800 can do that. Outside of the NAFLD, which there's no disputing, if you fix NAFLD, you've improved a

02:31:23.380 person's life. Does it matter if homocysteine goes down? Does it matter if you're at six instead of

02:31:29.180 14 because you've optimized these things? I don't think we're going to... Ginger, by the way.

02:31:33.820 Ginger is the other day. It's Sarah, Ginger, Bang Bang, Go-Go, RR Chick.

02:31:38.100 Yeah, I would still feel left out if I was Sarah.

02:31:40.020 Yeah, yeah, no.

02:31:40.900 Okay, so to the skeptic, no. I don't think the argument is super, super strong that by fixing the

02:31:45.900 homocysteine... You're reducing cardiovascular risk.

02:31:48.660 That's definitely not an airtight argument. I look at homocysteine and I say, well, look,

02:31:53.860 young healthy people have a homocysteine on average between seven and nine. That's probably the sweet

02:31:57.660 spot. But yeah, I mean, if I were looking at that from the perspective of what is the least stuff I can

02:32:06.520 do unless I am very compelled by the data to do it, then I would throw out at least everything that

02:32:16.260 I just said except the choline. And depending on how hard of a skeptic I am, I'd probably throw out

02:32:20.940 the choline too. And that's because this comes down to a philosophical question of what is the level of

02:32:26.960 evidence that you need to take an action? Versus the level of evidence to not take an action,

02:32:31.680 which people always forget that they have to ask that question just as well.

02:32:35.760 Well, also versus the level of evidence to state that you have a certain degree of certainty or

02:32:40.980 confidence in something. So the thing is, I think that we can be fairly... We will debate it, but I

02:32:47.860 think we can be fairly rational and within a fairly narrow window on what do we believe are the

02:32:55.220 principles that we need to secure to say we have a certain degree of confidence that something

02:33:01.620 is true. But we can never create that window for saying, what is the level of evidence that I

02:33:09.540 need in order to take an action? Because that comes back to your subjective values. A lot of this is

02:33:15.020 assumption as well. Even if you're coming to the question of what is the probability that we should

02:33:21.160 assess that something is true? For me, I would take as a background assumption that things that have

02:33:29.260 a proven track record in human history over a long period of time should be assumed as a default.

02:33:35.180 Someone else may take the assumption that nothing is the default or that the status quo is the default.

02:33:42.420 So if you're basically saying that we have to have meta-analyses of large randomized controlled

02:33:47.420 trials on clinical endpoints in order to have something, you are assuming that in the absence of

02:33:54.980 that evidence, we will follow the status quo. So even in the case of us debating how confident we

02:34:02.600 are that something is true, we have reasons like that to have a spectrum of agreement or disagreement.

02:34:07.720 But when it comes down to, should I take this supplement? That comes to subjective value over

02:34:14.660 what kind of risks do you want to take, right? So look, there are some people that want to optimize

02:34:21.640 their metabolism to make their body run like a well-oiled machine the best way that they know how,

02:34:27.660 and they're willing to spend some money or design their diet around doing so. And I think most of what I

02:34:36.160 said mostly applies to those people. I think for people who are looking for hard clinical endpoints,

02:34:42.680 and in fact, this is why there's Twitter wars over MTHFR sometimes, which is that they're really-

02:34:48.640 Thank God I miss those.

02:34:51.280 So yeah, so I mean, so I've gotten into some tussles on the internet with some people who

02:34:56.240 looked at this from the perspective of, look, there's no hard clinical endpoints for which

02:35:01.100 MTHFR is diagnostic. There's no hard clinical endpoints for which people with MTHFR, for whom that

02:35:08.580 population has some specific dietary or supplemental regimen that alters that clinical endpoint.

02:35:13.560 And I think that's true. Where I come from, if I were in that situation, I would want to bring my

02:35:19.840 homocysteine down to what by all probability appears to be the healthy level. If I were that

02:35:24.080 person, I would want to reason, well, I feel like my mind is too sticky and I want to loosen it up a

02:35:29.340 little bit. If I were that person, I would want to have good energy, and I would want to use a rational

02:35:35.000 assessment of why my energy might be low and what I can do to bring it up to normal. And I'm probably

02:35:40.280 never going to convince anyone that if I feel better, that there's a hard testable clinical endpoint

02:35:46.840 to that. Let's come back to the NR. I did a-

02:35:49.600 I was just about to say, the one thing I really want to ask you about is in all of this stuff,

02:35:53.300 whether it's the increased choline, the glycine, the creatine, I think I get the sense where you

02:36:01.420 on your own personal spectrum of risk fall on those. I haven't actually got a sense of where you

02:36:06.900 fall on the NR spectrum. Personally? Yeah. Oh, well, if it helps clarify, I took 75 micrograms

02:36:13.940 of it with breakfast and 75 micrograms with lunch. Micrograms? Milligrams, sorry. Which is still pretty

02:36:20.820 low. I mean, that's much lower than what's provided in those supplements. Right. I got 150 milligram

02:36:25.960 capsules that I broke in half. Okay. So that's much less than what's being provided in basis and

02:36:31.360 true niagen, right? Yeah, I might go up. I'm just playing around with it. It's just a tinkering thing.

02:36:36.120 With or without a sirtuin activator? Yeah, it's the true niagen. There's no

02:36:41.520 terastilbene in it. I was studying it a lot, so I figured, let me take it and see what happens.

02:36:48.780 Which, by the way, to me is one of the most tried and true interesting ways to do science is to,

02:36:53.660 you have to become a little bit of a self-experimenter on this stuff.

02:36:56.540 Well, H. pylori. Yeah. Everybody loves to point to that example. I will say this anecdotally,

02:37:02.400 for the patients of mine who do religiously take one of those two products, basis or true

02:37:08.120 niagen, the one thing that seems to across the board improve, and it would be very difficult to

02:37:14.620 attribute this to placebo, is patients who have even an inkling of rosacea seem to have a monumental

02:37:22.520 improvement. And again, I don't know if that has to do with the skin. We were talking about the skin

02:37:27.540 again. Is it sun-sensitive? Rosacea often is, but I don't know if I can say across the board if each

02:37:35.560 of those patients has rosacea. No, I wouldn't say it's exclusively sun-sensitive, right? So some people,

02:37:40.560 their rosacea gets amplified by certain things in their diet. I have some patients, when they eat

02:37:45.080 chocolate, it goes off the rails, or alcohol, or stress, or sleep deprivation. So no, I would say

02:37:50.840 there could be multiple different triggers for it. And I remember once even looking it up and finding

02:37:55.740 sort of an old esoteric paper about topical niacin, I believe. I think it was in the form of

02:38:01.200 niacin that could improve rosacea. I said before, I think that the skin is one of the areas where I

02:38:07.540 would expect to see fast results. And so it's this question of how do you pick the right people and

02:38:13.940 design the right study to see an effect like that. And so that's interesting. Maybe a rosacea

02:38:17.920 endpoint in a clinical study would have good results to it. Yeah. But what I'm basically taking away from

02:38:22.840 you is IVNAD is not a great idea. Just on the principles we've described, that does not seem

02:38:29.980 to be the way you want to administer it. It's much better to build up a hepatic reservoir of

02:38:35.420 nicotinamide that's converted through the NR that you can then slow trickle into circulation as needed

02:38:42.020 is probably a better bet. Yeah. I mean, I would consider it fascinating to see studies of what is

02:38:47.680 actually happening physiologically when people inject it. But nothing about... But outside of

02:38:52.560 that granulocyte response, which some people take that to mean it's doing great things. Like,

02:38:57.120 look at how shitty I feel. This must be doing something right. I've always taken that to mean,

02:39:00.980 I don't know. That's why mercury was so successful back in the day. Yeah. I mean,

02:39:06.840 it makes no physiological sense. But yeah, I mean, a study could prove me wrong, but there are no studies

02:39:11.460 and it makes no physiological sense. But I want to come back to one little point on the

02:39:15.680 decision-making thing. So the nicotinamide riboside video that I made, it took an anecdote

02:39:22.520 of someone who posted on my Facebook on something else that I was doing and told like a four-paragraph

02:39:28.980 story about how she started taking the truniogen and she felt great for a couple of weeks. But then

02:39:35.280 she started feeling the energy sapping off and then dropping. And then she felt like going through a

02:39:40.720 mental rollercoaster. And I used this anecdote that obviously could have other explanations and

02:39:46.900 clearly has no clinical measurable endpoint. And I got... People just came out of the woodwork.

02:39:54.080 Meaning pissed off.

02:39:55.240 Yeah. Trolling. Like in the YouTube comments.

02:39:58.060 YouTube comments should be never read.

02:40:00.860 But no, but I think... Listen, I think this is an interesting contrast anecdote. So here,

02:40:06.400 there are people often pointing out that there's no hard data in that story who are saying all kinds

02:40:15.900 of great things about the way they feel when they take a lot of this stuff.

02:40:20.220 Not realizing the irony.

02:40:21.560 Also not... Yeah. So I think it's irony, but it also comes back to the point where, look,

02:40:27.020 people are going to make a decision to take this or not. And there is no clear data on what it does.

02:40:31.900 And so you either take the position that you're going to wait 10 or 20 years until we know something

02:40:37.360 better, or you take the position that you're going to tinker. And if you're going to tinker,

02:40:40.960 you're going to tinker a lot more successfully if you have a working model of what's going on than

02:40:45.380 if you don't.

02:40:46.860 Yeah. I mean, I think it comes down to... And it would be impossible for me to say I don't

02:40:51.160 subscribe to that ethos because... I mean, look, I take rapamycin for heaven's sakes. And if you want

02:40:55.680 to talk about a much bigger hammer, I mean, rapa would probably be the single most out there thing

02:41:02.040 that I do. But my model's robust. Now, I also think I have much more data to point to. So even

02:41:07.760 though people could say, well, oh my God, rapamycin is so scary. I get to point to what happens in the

02:41:13.940 yeast, the flies, the worms, the mice, the rats, the dogs, the kangaroos, the humans. So I feel like

02:41:22.640 I'm standing on the shoulder of much more evidence, even though I'm interfering with a much more

02:41:28.100 important sensor, right? I'm actually going after the God sensor, right? Like the single most important

02:41:33.720 nutrient sensor in our body. But at the same time, you don't feel anything, right? So what's

02:41:38.700 interesting is if you're taking nicotinamide riboside for a way you feel, it's very confusing

02:41:45.600 because I don't see how one can disentangle the placebo effect. I mean, I think this has become

02:41:51.300 something that has come to the public's consciousness much more. I mean, even the New York

02:41:54.820 Times wrote a piece on this several months ago, which is the power of the placebo effect. And

02:42:00.780 I've even spoken with PIs who have run studies using psychoactive agents, and you'd think, how could

02:42:07.400 you placebo your way out of that? And yet they've told me that the placebo effect in terms of the

02:42:14.940 post-depression you would get with certain psychoactives is actually greater in the placebo group

02:42:19.700 than the treatment group. So I just don't know that I trust myself to discriminate between something

02:42:26.840 that works or doesn't work based on how I feel. I'd almost prefer to experiment with compounds where

02:42:34.400 I'm just pointing to biochemistry and, you know, hopefully in time, some biochemical proxies. Of

02:42:41.160 course, with rapamycin, we don't have a great biochemical proxy. We can't measure autophagy. We can't

02:42:47.860 count our senescent cells. You know, we can't look at inflammation within our muscles, things that

02:42:53.420 we believe would be improving. But I just don't like the idea of having to rely on how I feel

02:42:58.360 solely. I mean, look, if you feel like crap, whether it's placebo or not, that's reason to stop.

02:43:06.000 Yeah. Or if you feel like crap and then you take something that makes you feel great,

02:43:09.580 that's placebo. Leverage it.

02:43:10.920 Yeah. Although, again, look, I mean, you could argue that taking heroin will transiently make

02:43:15.240 you feel pretty good too. And that's sort of a dumb example because it's so over the top. But

02:43:19.640 so Peter Thiel has this great question that he poses in, I don't remember if he posed it in the

02:43:25.260 book, you know, zero to one or he certainly talked about this, which is what's the important truth

02:43:30.580 that very few people would agree with you on? So something that you think is definitively the

02:43:37.200 case or probabilistically very likely to be certain that you would find very few people to agree with

02:43:42.580 you on. And this doesn't have to be just limited to what we talked about today. This could be

02:43:46.840 should it be limited to health and medicine? No.

02:43:49.620 Okay, then I think that's easy. The thing that I believe strongly about that the largest number

02:43:54.980 would people would think I was crazy for it probably be that I'm twice the libertarian of

02:44:00.100 your libertarian uncle.

02:44:00.880 I don't know. I think you'd find a lot of people that more and more now are losing faith in big

02:44:08.300 government and would probably come to your aid on that. Maybe not.

02:44:11.760 I believe there would be a few hundred. Yeah.

02:44:14.180 You're that extreme in your libertarian views. All right. Well, then it's appropriate I phrase

02:44:18.400 this question through the lens of Peter. What about within the world of biochemistry, medicine,

02:44:22.480 et cetera?

02:44:22.740 So I think it's a very population-specific thing. So for me, I believe certain things

02:44:30.340 in the alternative health sphere that I think I'm surrounded by people that disagree with me

02:44:35.360 on and I spend a lot of time there that other people in the conventional sphere might think I'm

02:44:41.340 totally right for and vice versa. So as an example, in the alternative health sphere,

02:44:48.200 it is almost universal- By the way, am I in the alternative health

02:44:52.360 sphere or not? I don't know where I live.

02:44:54.120 Probably. Yeah.

02:44:55.160 Wow. Jeez. Sounds so bad.

02:44:57.160 So I think alternative medicine, it doesn't really have a clear definition. Like the NIH

02:45:01.380 has an arm of alternative medicine, but alternative medicine is basically the stuff that's not standard

02:45:07.720 practice. And then when it becomes standard practice, it's not alternative anymore.

02:45:11.600 Okay. Fair enough.

02:45:12.300 So by one definition, you could kind of encompass everyone who's doing something progressive or on

02:45:17.900 the edge or whatever. I mean, to the extent we would disagree with that, I would probably just

02:45:21.380 modify my definition here. But so I find myself in the nutrition sphere. I find myself among many

02:45:28.280 people who would throw out the RDAs, for example. So I would say people in nutrition that they're not

02:45:35.340 RDs, they're fairly progressive or they're fairly alternative or they're into supplementation or

02:45:39.640 whatever, probably think that the RDAs are trash science. And I think that the RDAs are actually

02:45:44.060 super good science. They're often outdated. They're often limited by the fact that if you

02:45:49.420 are a committee who's producing a report that someone else is going to simplify onto a four-inch

02:45:55.400 square on the side of the boxes of the cereal, that everyone in the 300 million Americans are going

02:46:01.300 to just look at the number and make some assumptions about that you have to be a lot more careful about

02:46:06.120 what you say. But I think that we really throw the baby out with the bathwater if we don't look at

02:46:13.180 what's been done by the people who are hardcore conventionals. This is your history coming back

02:46:18.820 to you, right? Your appreciation for the history of how these things came about? I mean, it's not just

02:46:23.140 history. I mean, for right now, one of the first things that I did when I started researching

02:46:26.620 niacin was I read the DRI report for niacin, which was in 1998. There's a lot that you could say to

02:46:32.400 criticize it. But I think that wherever you are in controversy, that you really have to know the

02:46:37.740 core of what constitutes the conventional belief. Just look at my Twitter feed over the last few

02:46:43.620 days. I'm in an environment where many people are convinced about the carbohydrate hypothesis of

02:46:51.200 obesity. And in fact, one of the interesting things about me is that I think I've found myself

02:46:56.500 very friendly with people in the low-carb community because of things that I think are crazy in the

02:47:04.780 conventional community that we agree on. So for example, I think the history of the dietary

02:47:12.320 guidelines and the demonization of saturated fat and cholesterol in the diet is completely wrong.

02:47:18.220 And I've done a lot on that to the point where I think probably both of us, for the amount of eggs

02:47:23.440 that we consume, there is a very large number of colleagues of ours who might think that we're

02:47:29.080 crazy. And let's take the example of the carbohydrate hypothesis of obesity. So I went into graduate school

02:47:36.960 thinking that insulin was the cause of obesity and that you couldn't store fats in adipose tissue unless

02:47:46.360 you had glucose there available and kind of all these things. And I also went in thinking that the

02:47:51.500 chain of causality was from metabolic problems to obesity. And I couldn't figure out why on earth my

02:47:58.720 professors seemed to think that the causal chain was opposite and that obesity was causing metabolic

02:48:03.100 dysfunction. I think I've come to really believe that the conventional view of obesity being a cause of

02:48:12.160 metabolic dysfunction is true. And that puts me square in the middle of conventional theory on a lot of

02:48:20.000 metrics. And because of the environment that I've put myself in with the people that I'm friends

02:48:26.640 with and colleagues with in that particular environment, I think it's a truth that a lot of

02:48:30.540 people find me crazy for.

02:48:32.500 Yeah, it's interesting. I mean, yeah, I've never really thought about where I said, I mean, you know,

02:48:37.460 so my view is that obesity is actually largely a compensatory response for something metabolic.

02:48:43.720 So that's the opposite view of you, I think, if I'm understanding you correctly. But it's also hard to neatly

02:48:49.180 fit these views into a box. I mean, because you're always going to find a patient that's an exception

02:48:54.120 to your rule. But that's a whole separate story. There's a lot more I'd like to go into. But we have

02:48:59.940 been at this for about three hours. So we might just have to do a round two at some point. In the

02:49:05.460 interim, what is the best place for people to find you? I know you're pretty active on social media

02:49:10.020 where how do you like to engage?

02:49:11.620 So my website is chrismasterjohnphd.com. Everything I do is posted there. I'm on Facebook,

02:49:18.240 Twitter, Instagram, and YouTube are the main places to find me. Twitter is a good place.

02:49:23.340 And your handle is?

02:49:24.880 At chrismasterjohn on all of those.

02:49:27.260 But not chrismasterjohnphd. That's only your website.

02:49:30.560 Yeah, I would have made it chrismasterjohn.com. But when I decided to buy it, there was someone who

02:49:36.860 bought it years ago and was selling the domain name for like $50,000 or something. And I said,

02:49:41.780 I'll just add the PhD.

02:49:44.040 That's why mine has MD, by the way. I didn't want to pay for the regular one.

02:49:47.960 A lot of the stuff we've talked about, this will be some pretty robust show notes because we've got

02:49:52.640 to, there's so much stuff to link to. As you pointed out, so many of these things are not as

02:49:58.300 difficult to, I don't want to say easy, but they're not as difficult to understand when you can

02:50:02.000 see the diagrams.

02:50:02.940 Yeah, for sure.

02:50:03.240 You've done some really elegant videos on a number of these topics, which we'll link to.

02:50:08.420 And I just want to thank you for being here, man.

02:50:10.680 Yeah, thank you for having me. It was great.

02:50:12.100 How was that Topo Chico, by the way? That was your first.

02:50:14.200 It was great. It has a slight taste of beer to me.

02:50:18.400 Interesting. I promise I didn't spike it. So I'm glad. Whenever I can give someone their

02:50:23.440 first Topo Chico, it is such a feeling of gratification. So I'm really glad.

02:50:28.920 Thank you so much.

02:50:29.760 All right, man.

02:50:30.080 You can find all of this information and more at peteratiamd.com forward slash podcast.

02:50:37.520 There you'll find the show notes, readings, and links related to this episode. You can also find

02:50:42.600 my blog at peteratiamd.com. Maybe the simplest thing to do is to sign up for my subjectively

02:50:47.860 non-lame once a week email, where I'll update you on what I've been up to, the most interesting

02:50:52.340 papers I've read, and all things related to longevity, science, performance, sleep, et cetera.

02:50:57.240 On social, you can find me on Twitter, Instagram, and Facebook, all with the ID peteratiamd. But

02:51:03.620 usually Twitter is the best way to reach me to share your questions and comments. Now for the

02:51:07.740 obligatory disclaimer, this podcast is for general informational purposes only and does not constitute

02:51:12.380 the practice of medicine, nursing, or other professional healthcare services, including the

02:51:17.280 giving of medical advice. And note, no doctor-patient relationship is formed. The use of this information

02:51:23.360 and the materials linked to the podcast is at the user's own risk. The content of this podcast is

02:51:28.440 not intended to be a substitute for professional medical advice, diagnoses, or treatment. Users should

02:51:33.820 not disregard or delay in obtaining medical advice for any medical condition they have and should seek

02:51:38.780 the assistance of their healthcare professionals for any such conditions. Lastly, and perhaps most

02:51:44.300 importantly, I take conflicts of interest very seriously. For all of my disclosures, the companies I invest

02:51:49.700 in and or advise, please visit peteratiamd.com forward slash about.

The Peter Attia Drive - March 25, 2019

#46 - Chris Masterjohn, Ph.D.： Navigating the many pathways to health and disease - NAD and sirtuins, methylation, MTHFR and COMT, choline deficiency and NAFLD, TMAO, creatine, and more

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